Morpholinyl containing benzimidazoles as inhibitors of respiratory syncytial virus replication

ABSTRACT

The present invention concerns morpholinyl containing benzimidazoles having inhibitory activity on the replication of the respiratory syncytial virus and having the formula 
                         
a prodrug, N-oxide, addition salt, quaternary amine, metal complex or stereochemically isomeric form thereof wherein G is a direct bond or optionally substituted C 1-10 alkanediyl; R 1  is Ar 1  or a monocyclic or bicyclic heterocycle Q is R 7 , pyrrolidinyl substituted with R 7 , piperidinyl substituted with R 7  or homopiperidinyl substituted with R 7 ; one of R 2a  and R 3a  is selected from halo, optionally mono- or polysubstituted C 1-6 alkyl, optionally mono- or polysubstituted C 2-6 alkenyl, nitro, hydroxy, Ar 2 , N(R 4a R 4b ), N(R 4a R 4b )sulfonyl, N(R 4a R 4b )carbonyl, C 1-6 alkyloxy, Ar 2 oxy, Ar 2 C 1-6 alkyloxy, carboxyl, C 1-6 alkyloxycarbonyl, or —C(=Z)Ar 2 ; and the other one of R 2a  and R 3a  is hydrogen; in case R 2a  is different from hydrogen then R 2b  is hydrogen, C 1-6 alkyl or halogen and R 3b  is hydrogen; in case R 3a  is different from hydrogen then R 3b  is hydrogen, C 1-6 alkyl or halogen and R 2b  is hydrogen. It further concerns the preparation thereof and compositions comprising these compounds, as well as the use thereof as a medicine.

This application is a National Stage application under 35 U.S.C. 371 of Application No. PCT/EP2004/053620 filed Dec. 20, 2004, which claims priority from European Patent Application No. EP03104810.1 filed Dec. 18, 2003, European Patent Application No. EP04105312.5 filed Oct. 26, 2004, and U.S. Provisional Application No. 60/567 182 filed Apr. 30, 2004, the contents of all of which are hereby incorporated by reference.

The present invention is concerned with morpholinyl containing benzimidazoles having antiviral activity, in particular, having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). It further concerns the preparation thereof and compositions comprising these compounds.

Human RSV or Respiratory Syncytial Virus is a large RNA virus, member of the family of Paramyxoviridae, subfamily pneumoviridae together with bovine RSV virus. Human RSV is responsible for a spectrum of respiratory tract diseases in people of all ages throughout the world. It is the major cause of lower respiratory tract illness during infancy and childhood. Over half of all infants encounter RSV in their first year of life, and almost all within their first two years. The infection in young children can cause lung damage that persists for years and may contribute to chronic lung disease in later life (chronic wheezing, asthma). Older children and adults often suffer from a (bad) common cold upon RSV infection. In old age, susceptibility again increases, and RSV has been implicated in a number of outbreaks of pneumonia in the aged resulting in significant mortality.

Infection with a virus from a given subgroup does not protect against a subsequent infection with an RSV isolate from the same subgroup in the following winter season. Re-infection with RSV is thus common, despite the existence of only two subtypes, A and B.

Today only three drugs have been approved for use against RSV infection. A first one is ribavirin, a nucleoside analogue, provides an aerosol treatment for serious RSV infection in hospitalized children. The aerosol route of administration, the toxicity (risk of teratogenicity), the cost and the highly variable efficacy limit its use. The other two drugs, RespiGam® and palivizumab, polyclonal and monoclonal antibody immunostimulants, are intended to be used in a preventive way.

Other attempts to develop a safe and effective RSV vaccine have all met with failure thus far. Inactivated vaccines failed to protect against disease, and in fact in some cases enhanced disease during subsequent infection. Life attenuated vaccines have been tried with limited success. Clearly there is a need for an efficacious non-toxic and easy to administer drug against RSV replication.

Previously, benzimidazoles and imidazopyridines as inhibitors of RSV replication have been described in WO 01/00611, WO 01/00612 and WO 01/00615.

Several series of benzimidazolyl and imidazopyridinyl piperidines have been described in patents, patent applications and publications of janssen Pharmaceutica N.V. as compounds possessing antihistaminic properties. See for example EP-A-5 318, EP-A-99 139, EP-A-145 037, WO-92/01687, Janssens F. et al. in Journal of Medicinal Chemistry, Am. Chem. Soc., Vol. 28, no. 12, pp. 1934-1943 (1985).

The present invention concerns inhibitors of RSV replication, which can be represented by formula (I)

their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms wherein

-   -   G is a direct bond or C₁₋₁₀alkanediyl optionally substituted         with one or more substituents individually selected from the         group of substituents consisting of hydroxy, C₁₋₆alkyloxy,         Ar¹C₁₋₆alkyloxy, C₁₋₆alkylthio, Ar¹C₁₋₆alkylthio,         HO(—CH₂—CH₂—O)_(n)—, C₁₋₆alkyloxy(-CH₂—CH₂—O)_(n)— or         Ar¹C₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—;     -   R¹ is Ar¹ or a monocyclic or bicyclic heterocycle being selected         from piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyridazinyl,         pyrimidinyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl,         thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl,         isoxazolyl, oxadiazolyl, quinolinyl, quinoxalinyl, benzofuranyl,         benzothienyl, benzimidazolyl, benzoxazolyl, benzthiazolyl,         pyridopyridyl, naphthiridinyl, 1H-imidazo[4,5-b]pyridinyl,         3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]-pyridinyl,         2,3-dihydro-1,4-dioxino[2,3-b]pyridyl or a radical of formula

-   -   wherein each of said monocyclic or bicyclic heterocycles may         optionally be substituted with 1 or where possible more, such as         2, 3, 4 or 5, substituents individually selected from the group         of substituents consisting of halo, hydroxy, amino, cyano,         carboxyl, C₁₋₆alkyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,         C₁₋₆alkyloxyC₁₋₆alkyl, Ar¹, Ar¹C₁₋₆alkyl, Ar¹C₁₋₆alkyloxy,         hydroxyC₁₋₆alkyl, mono-or di(C₁₋₆alkyl)amino, mono-or         di(C₁₋₆alkyl)aminoC₁₋₆alkyl, polyhaloC₁₋₆alkyl,         C₁₋₆alkylcarbonylamino, C₁₋₆alkyl-SO₂—NR^(5c)—,         Ar¹—SO₂—NR^(5c)—, C₁₋₆alkyloxycarbonyl, —C(═O)—NR^(5c)R^(5d),         HO(—CH₂—CH₂—O)_(n)—, halo(—CH₂—CH₂—O)_(n)—,         C₁₋₆allyloxy(—CH₂—CH₂—O)_(n)—, Ar¹C₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—         and mono-or di(C₁₋₆alkyl)amino(—CH₂—CH₂—O)_(n)—;

each n independently is 1, 2, 3 or 4;

each m independently is 1 or 2;

each p independently is 1 or 2;

each t independently is 0, 1 or 2;

Q is R⁷, pyrrolidinyl substituted with R⁷, piperidinyl substituted with R⁷ or homo-piperidinyl substituted with R⁷ wherein

R⁷ is C₁₋₆alkyl substituted with a heterocycle or R⁷ is C₁₋₆alkyl substituted with both a radical —OR⁸ and a heterocycle, wherein said heterocycle is selected from the group consisting of oxazolidine, thiazolidine, 1-oxo-thiazolidine, 1,1-dioxothiazolidine, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxothiomorpholinyl, hexahydrooxazepine, hexahydrothiazepine, 1-oxo-hexahydrothiazepine, 1,1-dioxo-hexahydrothiazepine; wherein each of said heterocyle may be optionally substituted with one or two substituents selected from the group consisting of C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, hydroxy, carboxyl, C₁₋₄alkyloxycarbonyl, aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl, C₁₋₄alkylcarbonylamino, aminosulfonyl and mono- or di(C₁₋₄alkyl)aminosulfonyl;

R⁸ is hydrogen, C₁₋₆alkyl or Ar¹C₁₋₆alkyl;

-   -   one of R^(2a) and R^(3a) is selected from halo, optionally mono-         or polysubstituted C₁₋₆alkyl, optionally mono- or         polysubstituted C₂₋₆alkenyl, nitro, hydroxy, Ar²,         N(R^(4a)R^(4b)), N(R^(4a)R^(4b))sulfonyl,         N(R^(4a)R^(4b))carbonyl, C₁₋₆alkyloxy, Ar²oxy, Ar²C₁₋₆alkyloxy,         carboxyl, C₁₋₆alkyloxycarbonyl, or —C(═Z)Ar²; and the other one         of R^(2a) and R^(3a) is hydrogen;         -   wherein         -   ═Z is ═O, ═CH—C(═O)—NR^(5a)R^(5b), ═CH₂, ═CH—C₁₋₆alkyl,             ═N—OH or ═N—O—C₁₋₆alkyl; and         -   the optional substituents on C₁₋₆alkyl and C₂₋₆alkenyl can             be the same or can be different relative to one another, and             are each independently selected from the group of             substituents consisting of hydroxy, cyano, halo, nitro,             N(R^(4a)R^(4b)), N(R^(4a)R^(4b))sulfonyl, Het, Ar²,             C₁₋₆alkyloxy, C₁₋₆alkyl-S(═O)_(t), Ar²oxy, Ar²—S(═O)_(t),             Ar²C₁₋₆alkyloxy, Ar²C₁₋₆alkyl-S(═O)_(t), Het-oxy,             Het-S(═O)_(t), HetC₁₋₆alkyloxy, HetC₁₋₆alkyl-S(═O)_(t),             carboxyl, C₁₋₆alkyloxycarbonyl and —C(=Z)Ar²;     -   in case R^(2a) is different from hydrogen then R^(2b) is         hydrogen, C₁₋₆alkyl or halogen and R^(3b) is hydrogen;     -   in case R^(3a) is different from hydrogen then R^(3b) is         hydrogen, C₁₋₆alkyl or halogen and R^(2b) is hydrogen;     -   R^(4a) and R^(4b) can be the same or can be different relative         to one another, and are each independently selected from the         group of substituents consisting of hydrogen, C₁₋₆alkyl,         Ar²C₁₋₆alkyl, (Ar²)(hydroxy)C₁₋₆alkyl, Het-C₁₋₆alkyl,         hydroxyC₁₋₆alkyl, mono- and di-(C₁₋₆alkyloxy)C₁₋₆alkyl,         (hydroxyC₁₋₆alkyl)oxyC₁₋₆alkyl, Ar¹C₁₋₆alkyloxy-C₁₋₆alkyl,         dihydroxyC₁₋₆alkyl, (C₁₋₆alkyloxy)(hydroxy)C₁₋₆alkyl,         (Ar¹C₁₋₆alkyloxy)(hydroxy)C₁₋₆alkyl, Ar¹oxy-C₁₋₆alkyl,         (Ar¹oxy)(hydroxy)-C₁₋₆alkyl, aminoC₁₋₆alkyl, mono- and         di(C₁₋₆alkyl)amino-C₁₋₆alkyl, carboxyl-C₁₋₆alkyl,         C₁₋₆alkyloxycarbonylC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, mono- and         di(C₁₋₆alkyl)aminocarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,         (C₁₋₄alkyloxy)₂-P(═O)—C₁₋₆alkyl,         (C₁₋₄alkyloxy)₂P(═O)—O—C₁₋₆alkyl, aminosulfonyl-C₁₋₆alkyl, mono-         and di(C₁₋₆alkyl)aminosulfonyl-C₁₋₆alkyl, C₁₋₆alkylcarbonyl,         Ar²carbonyl, Het-carbonyl, Ar²C₁₋₆alkylcarbonyl,         Het-C₁₋₆alkylcarbonyl, C₁₋₆alkylsulfonyl, aminosulfonyl, mono-         and di(C₁₋₆alkyl)aminosulfonyl, Ar²sulfonyl,         Ar²C₁₋₆alkyl-sulfonyl, Ar², Het, Het-sulfonyl,         HetC₁₋₆alkylsulfonyl;     -   R⁵ is hydrogen or C₁₋₆alkyl;     -   R^(5a) and R^(5b) can be the same or can be different relative         to one another, and are each independently hydrogen or         C₁₋₆alkyl; or     -   R^(5a) and R^(5b) taken together may form a bivalent radical of         formula —(CH₂)_(s)— wherein s is 4 or 5;     -   R^(5c) and R^(5d) can be the same or can be different relative         to one another, and are each independently hydrogen or         C₁₋₆alkyl; or     -   R^(5c) and R^(5d) taken together may form a bivalent radical of         formula —(CH₂)_(s)— wherein s is 4 or 5;     -   Ar¹ is phenyl or phenyl substituted with 1 or more, such as 2, 3         or 4, substituents selected from halo, hydroxy, C₁₋₆alkyl,         hydroxyC₁₋₆alkyl, polyhaloC₁₋₆alkyl, and C₁₋₆alkyloxy;     -   Ar² is phenyl, phenyl annelated with C₅₋₇cycloalkyl, or phenyl         substituted with 1 or more, such as 2, 3, 4 or 5, substituents         selected from halo, cyano, C₁₋₆alkyl, Het-C₁₋₆alkyl,         Ar¹—C₁₋₆alkyl, cyanoC₁₋₆alkyl, C₂₋₆alkenyl, cyanoC₂₋₆alkenyl,         R^(6b)—O—C₃₋₆alkenyl, C₂₋₆alkynyl, cyanoC₂₋₆alkynyl,         R^(6b)—O—C₃₋₆alkynyl, Ar¹, Het, R^(6b)—O—, R^(6b)—S—,         R^(6c)—SO—, R^(6c)—SO₂—, R^(6b)—O—C₁₋₆alkyl-SO₂—,         —N(R^(6a)R^(6b)), polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,         polyhaloC₁₋₆alkylthio, R^(6c)—C(═O)—, R^(6b)—O—C(═O)—,         N(R^(6a)R^(6b))—C(═O)—, R^(6b)—O—C₁₋₁₀alkyl, R^(6b)—S—C₁₋₆alkyl,         R^(6c)—S(═O)₂—C₁₋₆alkyl, N(R^(6a)R^(6b))—C₁₋₆alkyl,         R^(6c)—C(═O)—C₁₋₆alkyl, R^(6b)—O—C(═O)—C₁₋₆alkyl,         N(R^(6a)R^(6b))—C(═O)—C₁₋₆alkyl, R^(6c)—C(═O)—NR^(6b)—,         R^(6c)—C(═O)—O—, R^(6c)—C(═O)—NR^(6b)—C₁₋₆alkyl,         R^(6c)—C(═O)—O—C₁₋₆alkyl, N(R^(6a)R^(6b))—S(═O)₂—, H₂N—C(═NH)—;     -   R^(6a) is hydrogen, C₁₋₆alkyl, Ar¹, Ar¹C₁₋₆alkyl,         C₁₋₆alkylcarbonyl, Ar¹carbonyl, Ar¹C₁₋₆alkylcarbonyl,         C₁₋₆alkylsulfonyl, Ar¹sulfonyl, Ar¹C₁₋₆alkylsulfonyl,         C₁₋₆alkyloxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono- or         di(C₁₋₆alkyl)aminoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,         (carboxyl)-C₁₋₆alkyl, (C₁₋₆alkyloxycarbonyl)-C₁₋₆alkyl,         aminocarbonylC₁₋₆alkyl, mono- and         di(C₁₋₆alkyl)aminocarbonylC₁₋₆alkyl, aminosulfonyl-C₁₋₆alkyl,         mono- and di(C₁₋₆alkyl)aminosulfonyl-C₁₋₆alkyl, Het,         Het-C₁₋₆alkyl, Het-carbonyl, Het-sulfonyl,         Het-C₁₋₆alkylcarbonyl;     -   R^(6b) is hydrogen, C₁₋₆alkyl, Ar¹ or Ar¹C₁₋₆alkyl;     -   R^(6c) is C₁₋₆alkyl, Ar¹ or Ar¹C₁₋₆alkyl;     -   Het is a heterocycle being selected from tetrahydrofuranyl,         tetrahydrothienyl, pyrrolidinyl, pyrrolidinonyl, furanyl,         thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl,         isothiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl,         piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, pyridyl,         pyrazinyl, pyridazinyl, pyrimidinyl, tetrahydroquinolinyl,         quinolinyl, isoquinolinyl, benzodioxanyl, benzodioxolyl,         indolinyl, indolyl, each of said heterocycle may optionally be         substituted with oxo, amino, Ar¹, C₁₋₄alkyl, aminoC₁₋₄alkyl,         Ar¹C₁₋₄alkyl, mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono- or         di(C₁₋₆alkyl)amino, (hydroxyC₁₋₆alkyl)amino, and optionally         further with one or two C₁₋₄alkyl radicals.

The invention relates to the use of a compound of formula (I), or a prodrug, N-oxide, addition salt, quaternary amine, metal complex and stereochemically isomeric form thereof, for the manufacture of a medicament for inhibiting RSV replication. Or the invention relates to a method of inhibiting RSV replication in a warm-blooded animal said method comprising the administration of an effective amount of a compound of formula (I), or a prodrug, N-oxide, addition salt, quaternary amine, metal complex and stereochemically isomeric form thereof.

In a further aspect, this invention relates to novel compounds of formula (I) as well as methods for preparing these compounds.

The term ‘prodrug’ as used throughout this text means the pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is the active drug as defined in the compounds of formula (I). The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8^(th) ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”, p. 13-15) describing prodrugs generally, is hereby incorporated. Prodrugs are characterized by a good aqueous solubility and bioavailability, and are readily metabolized into the active inhibitors in vivo.

The terms ‘polysubstituted C₁₋₆alkyl’ and ‘polysubstituted C₂₋₆alkenyl’ such as used in the definition of R^(2a) and R^(3a) meant to comprise C₁₋₆alkyl radicals having two or more substituents, for example two, three, four, five or six substituents, in particular two or three substituents, further in particular two substituents. The upper limit of the number of substituents is determined by the number of hydrogen atoms that can be replaced as well as by the general properties of the substituents such as their bulkiness, these properties allowing the skilled person to determine said upper limit.

The term ‘C₁₋₁₀alkanediyl optionally substituted with one or more substituents’ as used in the definition of G is meant to comprise C₁₋₁₀alkanediyl radicals having no, one, two or more substituents, for example no, one, two, three, four, five or six substituents, in particular no, one, two or three substituents, further in particular no, one or two substituents. Also here, the upper limit of the number of substituents is determined by the factors mentioned above.

As used in the foregoing and hereinafter, ‘polyhaloC₁₋₆alkyl’ as a group or part of a group, e.g. in polyhaloC₁₋₆alkyloxy, is defined as mono- or polyhalo substituted C₁₋₆alkyl, in particular C₁₋₆alkyl substituted with up to one, two, three, four, five, six, or more halo atoms, such as methyl or ethyl with one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. Also included are perfluoro C₁₋₆alkyl groups, which are C₁₋₆alkyl groups whereion all hydrogen atoms are replaced by fluoro atoms, e.g. pentafluoroethyl. In case more than one halogen atom is attached to an alkyl group within the definition of polyhaloC₁₋₄alkyl, the halogen atoms may be the same or different.

Each of the monocyclic or bicyclic heterocycles in the definition of R¹ may optionally be substituted with 1 or where possible more substituents, such as 2, 3, 4 or 5, substituents. In particular, said heterocycles may optionally be substituted with up to 4, up to 3, up to 2 substituents, or up to 1 substituent.

Each Ar¹ or Ar² may be unsubstituted phenyl or phenyl substituted with 1 or more substituents, such as 5 or 4 substituents or, which is preferred, up to 3 substituents, or up to two substituents, or with one substituent.

A radical ‘R^(6b)—O—C₃₋₆alkenyl’ or ‘R^(6b)—O—C₃₋₆C₃₋₆alkynyl’ such as mentioned among the substituents of Ar² in particular has the R^(6b)—O— group on a saturated carbon atom.

A hydroxyC₁₋₆alkyl group when substituted on an oxygen atom or a nitrogen atom preferably is a hydroxyC₂₋₆alkyl group wherein the hydroxy group and the oxygen or nitrogen are separated by at least two carbon atoms.

A dihydroxyC₁₋₆alkyl group as mentioned for example in the definition of R^(4a) and R^(4b), is a C₁₋₆alkyl group having two hydroxy substituents which in particular are substituted on different carbon atoms. The terms (C₁₋₆alkyloxy)(hydroxy)C₁₋₆alkyl, di(C₁₋₆alkyl-oxy)C₁₋₆alkyl, (Ar¹C₁₋₆alkyloxy)(hydroxy)C₁₋₆alkyl refer to a C₁₋₆alkyl radical substitute with as well a C₁₋₆alkyloxy and a hydroxy group, with two C₁₋₆alkyloxy groups, and with a Ar¹C₁₋₆alkyloxy and a hydroxy group, respectively. Preferably in these radicals the substituents on the C₁₋₆alkyl group are on a carbon atom other than the carbon linked to the nitrogen atom to which R^(4a) and/or R^(4b) are linked.

As used herein C₁₋₃alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl and the like; C₁₋₄alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as the group defined for C₁₋₃alkyl and butyl and the like; C₂₋₄alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 2 to 4 carbon atoms such as ethyl, propyl, 1-methylethyl, butyl and the like; C₁₋₆alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the groups defined for C₁₋₄alkyl and pentyl, hexyl, 2-methylbutyl and the like; C₁₋₉alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 9 carbon atoms such as the groups defined for C₁₋₆alkyl and heptyl, octyl, nonyl, 2-methylhexyl, 2-methylheptyl and the like; C₁₋₁₀alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 10 carbon atoms such as the groups defined for C₁₋₉alkyl and decyl, 2-methylnonyl and the like.

The term ‘C₃₋₆alkenyl’ used herein as a group or part of a group is meant to comprise straight or branched chain unsaturated hydrocarbon radicals having at least one double bond, or preferably having one double bond, and from 3 to 6 carbon atoms such as propenyl, buten-1-yl, buten-2-yl, penten-1-yl, penten-2-yl, hexen-1-yl, hexen-2-yl, hexen-3-yl, 2-methylbuten-1-yl, and the like. The term ‘C₂₋₆alkenyl’ used herein as a group or part of a group is meant to comprise —C₃₋₆alkenyl groups and ethylene. The term ‘C₃₋₆alkynyl’ defines straight or branched chain unsaturated hydrocarbon radicals having one triple bond and from 3 to 6 carbon atoms such as propenyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 2-methylbutyn-1-yl, and the like. The term ‘C₂₋₆alkynyl’ used herein as a group or part of a group is meant to comprise C₃₋₆alkynyl groups and ethynyl.

C₃₋₇cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

C₂₋₅alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 2 to 5 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,2-propanediyl, 2,3-butanediyl, 1,5-pentanediyl and the like, C₁₋₄alkanediyl defines bivalent straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like; C₁₋₆alkanediyl is meant to include C₁₋₄alkanediyl and the higher homologues thereof having from 5 to 6 carbon atoms such as, for example, 1,5-pentanediyl, 1,6-hexanediyl and the like; C₁₋₁₀alkanediyl is meant to include C₁₋₆alkanediyl and the higher homologues thereof having from 7 to 10 carbon atoms such as, for example, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl and the like.

As used herein the term ‘R⁷ is C₁₋₆alkyl substituted with both a radical —OR⁸ and a heterocycle’ refers to a C₁₋₆alkyl radical bearing two substituents, i.e. the group —OR⁸ and a heterocycle and linked to the rest of the molecule through a carbon atom of the C₁₋₆alkyl moiety. Preferably the —OR⁸ group is linked to a carbon atom of the C₁₋₆alkyl moiety that is not adjacent (not in α-position) to a heteroatom (such as a nitrogen atom). More preferably the radical R⁷ being C₁₋₆alkyl substituted with both a radical —OR⁸ and a heterocycle’ is a radical that can be represented by the formula —CH₂—CH(OR⁸)—CH₂—.

The heterocycle in R⁷ preferably is linked to the group C₁₋₆alkyl via its nitrogen atom. The radicals hexahydrooxazepine, hexahydrothiazepine, 1-oxo-hexahydrothiazepine and 1,1-dioxo-hexahydrothiazepine preferably are 1,4-hexahydrooxazepine, 1,4-hexahydrothiazepine, 1-oxo-1,4-hexahydrothiazepine and 1,1-dioxo-1,4-hexahydrothiazepine.

As used herein before, the term (═O) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom and a sulfonyl moiety when two of said terms are attached to a sulfur atom. The term (═N—OH) forms a hydroxyimine moiety when attached to a carbon atom.

The term halo is generic to fluoro, chloro, bromo and iodo. As used in the foregoing and hereinafter, polyhaloC₁₋₆alkyl as a group or part of a group is defined as mono- or polyhalosubstituted C₁₋₆alkyl, in particular methyl with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl. In case more than one halogen atom is attached to an alkyl group within the definition of polyhaloC₁₋₄alkyl, the halogen atoms may be the same or different.

It should be noted that the radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable.

Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated. For instance pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl and 3-pentyl.

When any variable occurs more than one time in any constituent, each definition is independent.

Whenever used hereinafter, the term “compounds of formula (I)”, or “the present compounds” or similar term is meant to include the compounds of general formula (I), their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms. An interesting subgroup of the compounds of formula (I) or any subgroup thereof are the N-oxides, salts and all the stereoisomeric forms of the compounds of formula (I).

It will be appreciated that some of the compounds of formula (I) may contain one or more centers of chirality and exist as stereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore defines all the possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) may possess.

Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in pure form or in a mixture with each other are intended to be embraced within the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term ‘stereoisomerically pure’ concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms ‘enantiomerically pure’ and ‘diastereomerically pure’ should be understood in a similar way, but then having regard to the enantiomeric excess, respectively the diastereomeric excess of the mixture in question.

Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures. For instance, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid. Alternatively, enantiomers maybe separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

The diastereomeric racemates of formula (I) can be obtained separately by conventional methods. Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography.

For some of the compounds of formula (I), their prodrugs, N-oxides, salts, solvates, quaternary amines, or metal complexes and the intermediates used in the preparation thereof, the absolute stereochemical configuration was not experimentally determined. A person skilled in the art is able to determine the absolute configuration of such compounds using art-known methods such as, for example, X-ray diffraction.

The present invention is also intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

For therapeutic use, salts of the compounds of formula (I) are those wherein the counter-ion is pharmaceutically acceptable. However, salts of acids and bases, which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.

The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.

The term addition salt as used hereinabove also comprises the solvates, which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.

The term “quaternary amine” as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkyl halide, aryl halide or arylalkyl halide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethane sulfonates, alkyl methane sulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.

The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.

It will be appreciated that the compounds of formula (I) may have metal binding, chelating, complexating properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.

Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.

One embodiment of the present invention concerns compounds of formula (I-a):

wherein Q, R⁵, G, R¹, R^(2a), R^(2b) are as specified in the definitions of the compounds of formula (I) or any of the subgroups of compounds of formula (I) specified herein.

Another embodiment of the present invention concerns compounds of formula (I-b):

wherein Q, R⁵, G, R¹, R^(3a), R^(3b) are as specified in the definitions of the compounds of formula (I) or any of the subgroups of compounds of formula (I) specified herein.

One particular embodiment of the present invention concerns compounds of formula (I-a-1):

wherein Q, R⁵, G, R¹, R^(4a) and R^(2b) are as specified in the definitions of the compounds of formula (I) or any of the subgroups of compounds of formula (I) specified herein; and

Alk is C₁₋₆alkanediyl;

-   -   R⁹, R¹⁰, R¹¹ independently from one another have the same         meanings as the substituents on Ar² as specified in the         definitions of the compounds of formula (I) or of any of the         subgroups thereof; and R¹⁰ and/or R¹¹ may also be hydrogen.

Another particular embodiment of the present invention concerns compounds of formula (I-b-1):

wherein Q, R⁵, G, R¹, R^(4a) and R^(3b) are as specified in the definitions of the compounds of formula (I) or any of the subgroups of compounds of formula (I) specified herein; and

Alk is C₁₋₆alkanediyl;

R⁹, R¹⁰, R¹¹ independently from one another have the same meanings as the substituents on Ar² as specified in the definitions of the compounds of formula (I) or of any of the subgroups thereof; and R¹⁰ and/or R¹¹ may also be hydrogen.

Still other embodiments of the invention are groups of compounds which can be represented by formula:

wherein in (I-c) or in (I-d) radicals R⁵, G, R¹, R^(2a), R^(2b), R^(3a), R^(3b) are as specified in the definitions of the compounds of formula (I) or in any of the subgroups of compounds of formula (I) specified herein; and

Alk¹ is C₁₋₆alkanediyl;

R^(7a) is a heterocycle, the latter having the meanings of the heterocycle specified for radical R⁷ in the definitions of the compounds of formula (I) or in any of the subgroups of compounds of formula (I) specified herein.

Interesting subgroups are t hose comprising compounds of formulae:

wherein in (I-c-1), (I-c-2), (I-c-3), (I-c-4), (I-c-5), (I-c-6), (I-d-1) or (I-d-2) the radicals R⁵, G, R¹, R^(2a), R^(2b), R^(3a), R^(3b) are as specified in the definitions of the compounds of formula (I) or any of the subgroups of compounds of formula (I) specified herein; and the radicals Alk, Alk¹, R^(7a), R⁹, R¹⁰, R¹¹ are as specified above or in any of the subgroups of compounds of formula (I) specified herein; and in (I-c-5) and (I-c-6) R^(6a) and R^(6b) are as specified in the definitions of the compounds of formula (I) or any of the subgroups of compounds of formula (I) specified herein.

Preferred subgroups are those subgroups of compounds of formula (I) wherein R^(7a) is a heterocycle selected from the group consisting of oxazolidine, thiazolidine, morpholinyl, thiomorpholinyl, hexahydrooxazepine, hexahydrothiazepine; wherein each of said heterocyle may be optionally substituted with one or two substituents selected from the group consisting of C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, hydroxy, carboxyl, C₁₋₄alkyloxycarbonyl, aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl, C₁₋₄alkylcarbonylamino, aminosulfonyl and mono- or di(C₁₋₄alkyl)aminosulfonyl; or preferably, wherein each of said heterocyle may be optionally substituted with one or two substituents selected from the group consisting of C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, carboxyl, C₁₋₄alkyloxy-carbonyl, aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl; or more preferably wherein each of said heterocyle may be optionally substituted with one or two substituents selected from the group consisting of C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl.

More preferred subgroups are those subgroups of compounds of formula (I) wherein R^(7a) is a heterocycle, wherein said heterocycle is oxazolidine, thiazolidine, morpholinyl, or thiomorpholinyl, wherein each of said heterocyle may be optionally substituted with one or two substituents selected from the group consisting of C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, aminocarbonylC₁₋₆alkyl.

Further preferred subgroups are those subgroups of compounds of formula (I) wherein R^(7a) is a heterocycle, wherein said heterocycle is morpholinyl or thiomorpholinyl, wherein each of said heterocyle may be optionally substituted with one or two substituents selected from the group consisting of C₁₋₆alkyl, hydroxyC₁₋₆alkyl and aminocarbonyl-C₁₋₆alkyl.

Further preferred subgroups are those subgroups of compounds of formula (I) wherein R^(7a) is a heterocycle, wherein said heterocycle is morpholinyl, which may be optionally substituted with one or two substituents selected from the group consisting of C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminocarbonyl-C₁₋₆alkyl.

Most preferred subgroups are those subgroups of compounds of formula (I) wherein R^(7a) is morpholinyl.

Further preferred subgroups are those wherein Alk is ethylene or methylene, more preferably wherein Alk is methylene.

Further preferred subgroups are those wherein Alk¹ is C₁₋₄alkanediyl, more preferably wherein Alk¹ is C₂₋₃alkanediyl.

In (I-a-1), (I-b-1), (I-c-3) or (I-c-4) R^(4a) preferably is hydrogen, hydoxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl.

In (I-a-1), (I-b-1), (I-c) (I-d), (I-c-1), (I-c-2), (I-c-3), (I-c-4), (I-c-5), (I-c-6), (I-d-1) or (I-d-2) the radicals

-   -   R⁹, R¹⁰, R¹¹ preferably and independently from one another are         C₁₋₆alkyl or R^(6b)—O—C₁₋₆alkyl; and R¹⁰ and/or R¹¹ may also be         hydrogen; or     -   R⁹, R¹⁰ more preferably and independently from one another are         C₁₋₆alkyl or R^(6b)—O—C₁₋₆alkyl; and R¹¹ is hydrogen; or     -   R⁹, R¹⁰ still more preferably are C₁₋₆alkyl and R¹¹ is hydrogen;         or     -   R⁹ is C₁₋₆alkyl, R¹⁰ is R^(6b)—O—C₁₋₆alkyl and R¹¹ is hydrogen.

It is to be understood that the above defined subgroups of compounds of formulae (I-a), (I-b), etc. as well as any other subgroup defined herein are meant to also comprise any prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms of such compounds.

Particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein G is C₁₋₁₀alkanediyl, more in particular wherein G is methylene.

Other particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein

-   -   (a) R¹ is other than Ar¹; or wherein     -   (b) R¹ is Ar¹ or a monocyclic heterocycle, which is as specified         in the definitions of the compounds of formula (I) or any of the         subgroups thereof.

Further particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein

-   -   (c) R¹ is pyridyl optionally substituted with 1 or 2         substituents independently selected from the group consisting of         halo, hydroxy, amino, cyano, carboxyl, C₁₋₆alkyl, C₁₋₆alkyloxy,         C₁₋₆alkylthio, C₁₋₆alkyloxyC₁₋₆alkyl, Ar¹, Ar¹C₁₋₆alkyl,         Ar¹C₁₋₆alkyl-oxy, hydroxyC₁₋₆alkyl, mono-or di(C₁₋₆alkyl)amino,         mono-or di(C₁₋₆alkyl)amino-C₁₋₆alkyl, polyhaloC₁₋₆alkyl,         C₁₋₆alkylcarbonylamino, C₁₋₆alkyl-SO₂—NR^(4a)—,         Ar¹—SO₂—NR^(4a)—, C₁₋₆alkyloxycarbonyl, —C(═O)—NR^(4a)R^(4b),         HO(—CH₂—CH₂—O)_(n)—, halo(—CH₂—CH₂—O)_(n)—,         C₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—, Ar¹C₁₋₆alkyloxy(—CH₂—CH₂—O)_(n)—         and mono-or di(C₁₋₆alkyl)amino(—CH₂—CH₂—O)_(n)—; or more in         particular     -   (d) R¹ is pyridyl substituted with 1 or 2 substituents         independently selected from the group consisting of hydroxy,         C₁₋₆alkyl, halo, C₁₋₆alkyloxy, Ar¹C₁₋₆alkyloxy and         (C₁₋₆alkyloxy)C₁₋₆alkyloxy; preferably wherein     -   (e) R¹ is pyridyl substituted with 1 or 2 substituents         independently selected from the group consisting of hydroxy,         C₁₋₆alkyl, halo and C₁₋₆alkyloxy; or wherein     -   (f) R¹ is pyridyl substituted with 1 or 2 substituents         independently selected from the group consisting of hydroxy and         C₁₋₆alkyl; more preferably wherein     -   (g) R¹ is pyridyl substituted with hydroxy and C₁₋₆alkyl; or         more preferably wherein     -   (h) R¹ is pyridyl substituted with hydroxy and methyl; or         wherein     -   (i) R¹ is 3-hydroxy-6-methylpyrid-2-yl.

Further embodiments comprise those compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein

-   -   (j) R¹ is Ar¹, quinolinyl, benzimidazolyl, a radical of formula

-   -    pyrazinyl, or pyridyl; or wherein     -   (k) R¹ is Ar¹, quinolinyl, benzimidazolyl or a radical of         formula (c-4) wherein m is 2, pyrazinyl, or pyridyl;     -   wherein each of the radicals in (j) and (k) may optionally be         substituted with the substituents specified in the definition of         the compounds of formula (I) and in particular pyridyl may be         substituted as specified above in (a) to (i).

Further embodiments comprise those compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein

-   -   (l) R¹ is Ar¹, quinolinyl, benzimidazolyl or a radical of         formula (c-4) wherein m is 2, pyrazinyl, or pyridyl, wherein         each of these radicals may optionally be substituted with one,         two or three radicals selected from the group consisting of         halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, Ar¹C₁₋₆alkyloxy,         (C₁₋₆alkyloxy)C₁₋₆alkyloxy; or more specifically wherein     -   (m) R¹ is Ar¹, quinolinyl, benzimidazolyl or a radical of         formula (c-4) wherein m is 2, pyrazinyl, or pyridyl, wherein         each of these radicals may optionally be substituted with one,         two or three radicals selected from the group consisting of         halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, benzyloxy; or more         specifically wherein     -   (n) R¹ is phenyl optionally substituted with one, two or three         radicals selected from the group consisting of halo, hydroxy,         C₁₋₆alkyl, C₁₋₆alkyloxy; quinolinyl; a radical (c-4) wherein m         is 2, optionally substituted with up to two radicals selected         from C₁₋₆alkyl; benzimidazolyl optionally substituted with         C₁₋₆alkyl; pyridyl optionally substituted with one or two         radicals selected from hydroxy, halo, C₁₋₆alkyl, benzyloxy and         C₁₋₆alkyloxy, pyrazinyl optionally substituted with up to three         radicals selected from C₁₋₆alkyl; or pyridyl substituted or         optionally substituted as specified above in (a)-(i); or wherein     -   (o) R¹ is phenyl optionally substituted with one or two radicals         selected from the group consisting of halo, hydroxy, C₁₋₆alkyl,         C₁₋₆alkyloxy;     -   (p) R¹ is quinolinyl;     -   (q) R¹ is a radical (c-4) wherein m is 2, optionally substituted         with up to two radicals selected from C₁₋₆alkyl;     -   (r) R¹ is benzimidazolyl optionally substituted with C₁₋₆alkyl;         pyridyl optionally substituted with one or two radicals selected         from hydroxy, halo, C₁₋₆alkyl, benzyloxy and C₁₋₆alkyloxy,     -   (s) R¹ is pyrazinyl optionally substituted with up to three         radicals selected from C₁₋₆alkyl.

Preferred subgroups of compounds of formula (I) or any of the subgroups of compounds of formula (I) are those wherein G is a direct bond or methylene and R¹ is as specified above in (a)-(s). Further preferred are the compounds of formula (I) or any of the subgroups specified herein wherein G is a direct bond and R¹ is a radical (c-4), in particular wherein m is 2, optionally substituted with up to two radicals selected from C₁₋₆alkyl. Further preferred are the compounds of formula (I) or any of the subgroups specified herein wherein or G is methylene and R¹ is as specified above in (a)-(s), but is other than a radical (c-4).

Further particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein R⁵ is hydrogen.

Other particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein Q is R⁷.

Interesting compounds are those compounds of formula (I) or of any of the subgroups specified herein, wherein Q is R⁷ and the latter is C₁₋₆alkyl substituted with a heterocycle or R⁷ is C₁₋₆alkyl substituted with both a radical —OR⁸ and a heterocycle, wherein said heterocycle is selected from the group consisting of oxazolidine, thiazolidine, morpholinyl, thiomorpholinyl, hexahydrooxazepine, hexahydrothiazepine; wherein each of said heterocyle may be optionally substituted with one or two substituents selected from the group consisting of C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, hydroxy, carboxyl, C₁₋₄alkyloxycarbonyl, aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl, C₁₋₄alkylcarbonylamino, aminosulfonyl and mono- or di(C₁₋₄alkyl)aminosulfonyl; or preferably, wherein each of said heterocyle may be optionally substituted with one or two substituents selected from the group consisting of C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, carboxyl, C₁₋₄alkyloxycarbonyl, aminocarbonyl, mono- or di(C₁₋₄alkyl)aminocarbonyl; or more preferably wherein each of said heterocyle may be optionally substituted with one or two substituents selected from the group consisting of C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl.

An interesting subgroup of compounds are those compounds of formula (I) or of any of the subgroups specified herein, wherein Q is R⁷ and the latter is C₁₋₆alkyl substituted with a heterocycle or R⁷ is C₁₋₆alkyl substituted with both a radical —OR⁸ and a heterocycle, wherein said heterocycle is oxazolidine, thiazolidine, morpholinyl, or thiomorpholinyl, wherein each of said heterocyle may be optionally substituted with one or two substituents selected from the group consisting of C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, aminocarbonylC₁₋₆alkyl.

A further interesting subgroup of compounds are those compounds of formula (I) or of any of the subgroups specified herein, wherein Q is R⁷ and the latter is C₁₋₆alkyl substituted with a heterocycle or R⁷ is C₁₋₆alkyl substituted with both a radical —OR⁸ and a heterocycle, wherein said heterocycle is morpholinyl or thiomorpholinyl, wherein each of said heterocyle may be optionally substituted with one or two substituents selected from the group consisting of C₁₋₆alkyl, hydroxyC₁₋₆alkyl and aminocarbonyl-C₁₋₆alkyl.

Still a further interesting subgroup of compounds are those compounds of formula (I) or of any of the subgroups specified herein, wherein Q is R⁷ and the latter is C₁₋₆alkyl substituted with morpholinyl, which may be optionally substituted with one or two substituents selected from the group consisting of C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminocarbonyl-C₁₋₆alkyl, or preferably wherein Q is R⁷ and the latter is C₁₋₆alkyl substituted with morpholinyl.

Other particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein Q is pyrrolidinyl substituted with R⁷, piperidinyl substituted with R⁷ or homopiperidinyl substituted with R⁷; in particular wherein Q is piperidinyl substituted with R⁷.

Still other particular subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein Q is pyrrolidinyl substituted with R⁷, piperidinyl substituted with R⁷ or homopiperidinyl substituted with R⁷; in particular wherein Q is piperidinyl substituted with R⁷; wherein

-   -   (a) each R⁷ is C₁₋₆alkyl substituted with a heterocycle or R⁷ is         C₁₋₆alkyl substituted with both a radical —OR⁸ and a         heterocycle, wherein said heterocycle is oxazolidine,         thiazolidine, morpholinyl, thiomorpholinyl, hexahydrooxazepine,         or hexahydrothiazepine; wherein each of said heterocyle may be         optionally substituted with one or two substituents selected         from the group consisting of C₁₋₆alkyl, hydroxylC₁₋₆alkyl,         aminocarbonylC₁₋₆alkyl, hydroxy, carboxyl, C₁₋₄alkyloxycarbonyl,         aminocarbonyl, mono and di(C₁₋₄alkyl)aminocarbonyl,         C₁₋₄alkylcarbonylamino, aminosulfonyl and mono- or         di(C₁₋₄alkyl)aminosulfonyl; or preferably, wherein each of said         heterocyle may be optionally substituted with one or two         substituents selected from the group consisting of C₁₋₆alkyl,         hydroxyl-C₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, carboxyl,         C₁₋₄alkyloxycarbonyl, amino-carbonyl, mono and         di(C₁₋₄alkyl)aminocarbonyl; or more preferably wherein each of         said heterocyle may be optionally substituted with one or two         substituents selected from the group consisting of C₁₋₆alkyl; or     -   (b) wherein each R⁷ is C₁₋₆alkyl substituted with a heterocycle         or R⁷ is C₁₋₆alkyl substituted with both a radical —OR⁸ and a         heterocycle, wherein said heterocycle is oxazolidine,         thiazolidine, morpholinyl, or thiomorpholinyl, wherein each of         said heterocyle may be optionally substituted with one or two         substituents selected from the group consisting of C₁₋₆alkyl,         hydroxy-C₁₋₆alkyl and aminocarbonyl-C₁₋₆alkyl; or     -   (c) wherein each R⁷ is C₁₋₆alkyl substituted with a heterocycle         or R⁷ is C₁₋₆alkyl substituted with both a radical —OR⁸ and a         heterocycle, wherein said heterocycle is morpholinyl or         thiomorpholinyl, wherein each of said heterocyle may be         optionally substituted with one or two substituents selected         from the group consisting of C₁₋₆alkyl, hydroxyC₁₋₆alkyl and         aminocarbonylC₁₋₆alkyl; or     -   (d) wherein each R⁷ is C₁₋₆alkyl substituted with morpholinyl,         which may be optionally substituted with one or two substituents         selected from the group consisting of C₁₋₆alkyl,         hydroxyC₁₋₆alkyl, aminocarbonyl-C₁₋₆alkyl; or preferably     -   (e) wherein Q is R⁷ and the latter is C₁₋₆alkyl substituted with         morpholinyl.

Of particular interest are the compounds of formula (I) or any of the subgroups specified herein wherein R⁸ is hydrogen.

Other subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein

-   -   (a) R^(4a) and R^(4b) are each independently selected from         hydrogen, C₁₋₆alkyl, Ar²C₁₋₆alkyl, (Ar²)(hydroxy)C₁₋₆alkyl,         Het-C₁₋₆alkyl, hydroxyC₁₋₆alkyl, mono- and         di-(C₁₋₆alkyloxy)C₁₋₆alkyl, (hydroxyC₁₋₆alkyl)oxyC₁₋₆alkyl,         Ar¹C₁₋₆alkyloxy-C₁₋₆alkyl, dihydroxyC₁₋₆alkyl,         (C₁₋₆alkyloxy)(hydroxy)C₁₋₆alkyl,         (Ar¹C₁₋₆alkyloxy)(hydroxy)C₁₋₆alkyl, Ar¹oxyC₁₋₆alkyl,         (Ar¹oxy)(hydroxy)-C₁₋₆alkyl, aminoC₁₋₆alkyl, mono- and         di(C₁₋₆alkyl)amino-C₁₋₆alkyl, carboxylC₁₋₆alkyl,         C₁₋₆alkyloxycarbonyl-C₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, mono-         and di(C₁₋₆alkyl)aminocarbonyl-C₁₋₆alkyl,         C₁₋₆alkylcarbonylC₁₋₆alkyl, (C₁₋₄alkyloxy)₂P(═O)—C₁₋₆alkyl,         (C₁₋₄alkyloxy)₂P(═O)—O—C₁₋₆alkyl, aminosulfonyl-C₁₋₆alkyl, mono-         and di(C₁₋₆alkyl)aminosulfonyl-C₁₋₆alkyl, C₁₋₆alkylcarbonyl,         Ar²carbonyl, Het-carbonyl, Ar²C₁₋₆alkylcarbonyl,         Het-C₁₋₆alkylcarbonyl, Ar² and Het; or wherein     -   (b) R^(4a) and R^(4b) are each independently selected from         hydrogen, C₁₋₆alkyl, Ar²C₁₋₆alkyl, (Ar²)(hydroxy)C₁₋₆alkyl,         Het-C₁₋₆alkyl, hydroxyC₁₋₆alkyl, mono- and         di-(C₁₋₆alkyloxy)C₁₋₆alkyl, (hydroxyC₁₋₆alkyl)oxyC₁₋₆alkyl,         Ar¹C₁₋₆alkyloxy-C₁₋₆alkyl, dihydroxyC₁₋₆alkyl,         (C₁₋₆alkyloxy)(hydroxy)C₁₋₆alkyl,         (Ar¹C₁₋₆alkyloxy)(hydroxy)C₁₋₆alkyl, Ar¹oxy-C₁₋₆alkyl,         (Ar¹oxy)(hydroxy)-C₁₋₆alkyl, aminoC₁₋₆alkyl, mono- and         di(C₁₋₆alkyl)amino-C₁₋₆alkyl, carboxyl-C₁₋₆alkyl,         C₁₋₆alkyloxycarbonylC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, mono- and         di(C₁₋₆alkyl)aminocarbonylC₁₋₆alkyl, C₁₋₆alkylcarbonylC₁₋₆alkyl,         (C₁₋₄alkyloxy)₂-P(═O)—C₁₋₆alkyl,         (C₁₋₄alkyloxy)₂P(═O)—O—C₁₋₆alkyl, aminosulfonyl-C₁₋₆alkyl, mono-         and di(C₁₋₆alkyl)aminosulfonyl-C₁₋₆alkyl, Ar² and Het; or         wherein     -   (c) R^(4a) and R^(4b) are each independently selected from         hydrogen, C₁₋₆alkyl, Ar²C₁₋₆alkyl, (Ar²)(hydroxy)C₁₋₆alkyl,         Het-C₁₋₆alkyl, hydroxyC₁₋₆alkyl, (C₁₋₆alkyloxy)C₁₋₆alkyl,         (hydroxyC₁₋₆alkyl)oxyC₁₋₆alkyl, Ar¹C₁₋₆alkyloxy-C₁₋₆alkyl,         Ar¹oxy-C₁₋₆alkyl, (Ar¹oxy)(hydroxy)-C₁₋₆alkyl, aminoC₁₋₆alkyl,         mono- and di(C₁₋₆alkyl)amino-C₁₋₆alkyl, carboxylC₁₋₆alkyl,         C₁₋₆alkyloxycarbonyl-C₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, mono-         and di(C₁₋₆alkyl)aminocarbonyl-C₁₋₆alkyl,         (C₁₋₄alkyloxy)₂P(═O)—C₁₋₆alkyl,         (C₁₋₄alkyloxy)₂P(═O)—O—C₁₋₆alkyl, aminosulfonyl-C₁₋₆alkyl, mono-         and di(C₁₋₆alkyl)aminosulfonyl-C₁₋₆alkyl and Ar¹; or wherein     -   (d) R^(4a) and R^(4b) are each independently selected from         hydrogen, C₁₋₆alkyl, (Ar²)(hydroxy)C₁₋₆alkyl, Het-C₁₋₆alkyl,         hydroxyC₁₋₆alkyl, (C₁₋₆alkyloxy)C₁₋₆alkyl,         (hydroxyC₁₋₆alkyl)oxyC₁₋₆alkyl, Ar¹C₁₋₆alkyloxy-C₁₋₆alkyl,         Ar¹oxyC₁₋₆alkyl, (Ar¹oxy)(hydroxy)-C₁₋₆alkyl, aminoC₁₋₆alkyl,         mono- and di(C₁₋₆alkyl)amino-C₁₋₆alkyl, carboxylC₁₋₆alkyl,         aminocarbonylC₁₋₆alkyl, mono- and         di(C₁₋₆alkyl)-aminocarbonylC₁₋₆alkyl,         (C₁₋₄alkyloxy)₂P(═O)—C₁₋₆alkyl,         (C₁₋₄alkyloxy)₂-P(═O)—O—C₁₋₆alkyl, aminosulfonyl-C₁₋₆alkyl,         mono- and di(C₁₋₆alkyl)amino-sulfonyl-C₁₋₆alkyl and Ar¹.

Interesting subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein

-   -   (e) R^(4a) and R^(4b) are each independently selected from         hydrogen, morpholinyl-C₁₋₆alkyl, hydroxyC₁₋₆alkyl,         (C₁₋₆alkyloxy)C₁₋₆alkyl, aminoC₁₋₆alkyl, mono- and         di(C₁₋₆alkyl)amino-C₁₋₆alkyl, carboxylC₁₋₆alkyl,         aminocarbonylC₁₋₆alkyl, mono- and         di(C₁₋₆-alkyl)aminocarbonylC₁₋₆alkyl, aminosulfonyl-C₁₋₆alkyl,         mono- and di(C₁₋₆alkyl)aminosulfonyl-C₁₋₆alkyl and Ar¹; or         wherein     -   (f) R^(4a) and R^(4b) are each independently selected from         hydrogen, hydroxyC₁₋₆alkyl, (C₁₋₆alkyloxy)C₁₋₆alkyl,         aminoC₁₋₆alkyl, mono- and di(C₁₋₆alkyl)aminoC₁₋₆alkyl,         carboxylC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, mono- and         di(C₁₋₆alkyl)amino-carbonyl-C₁₋₆alkyl; or wherein     -   (g) R^(4a) and R^(4b) are each independently selected from         hydrogen, hydroxyC₁₋₆alkyl, aminocarbonylC₁₋₆alkyl, mono- and         di(C₁₋₆alkyl)aminocarbonylC₁₋₆alkyl; or wherein     -   (h) R^(4a) and R^(4b) are each independently selected from         hydrogen, hydroxyC₁₋₆alkyl and aminocarbonylC₁₋₆alkyl.

Other interesting subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein R^(4a) is hydrogen and R^(4b) is as specified above in the restricted definitions (a) to (h).

Other subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein

-   -   (a) Ar² is phenyl, phenyl annelated with C₅₋₇cycloalkyl, or         phenyl substituted with 1, 2, or 3 substituents selected from         halo, cyano, C₁₋₆alkyl, Het-C₁₋₆alkyl, Ar¹—C₁₋₆alkyl,         cyanoC₁₋₆alkyl, C₂₋₆alkenyl, cyanoC₂₋₆alkenyl,         R^(6b)—O—C₃₋₆alkenyl, C₂₋₆alkynyl, cyanoC₂₋₆alkynyl,         R^(6b)—O—C₃₋₆alkynyl, Ar¹, Het, R^(6b)—O—, R^(6b)—S—,         R^(6c)—SO—, R^(6c)—SO₂—, R^(6b)—O—C₁₋₆alkyl-SO₂—,         —N(R^(6a)R^(6b)), CF₃, CF₃-oxy, CF₃-thio, R^(6c)—C(═O)—,         R^(6b)—O—C(═O)—, N(R^(6a)R^(6b))—C(═O)—, R^(6b)—O—C₁₋₆alkyl,         R^(6b)—S—C₁₋₆alkyl, R^(6c)—S(═O)₂—C₁₋₆alkyl,         N(R^(6a)R^(6b))—C₁₋₆alkyl, R^(6c)—C(═O)—C₁₋₆alkyl,         R^(6b)—O—C(═O)—C₁₋₆alkyl, N(R^(6a)R^(6b))—C(═O)—C₁₋₆alkyl,         R^(6c)—C(═O)—NR^(6b), R^(6c)—C(═O)—O—,         R^(6c)—C(═O)—NR^(6b)—C₁₋₆alkyl, R^(6c)—C(═O)—O—C₁₋₆alkyl,         N(R^(6a)R^(6b))—S(═O)₂—, H₂N—C(═NH)—;     -   (b) Ar² is phenyl, phenyl annelated with C₅₋₇cycloalkyl, or         phenyl substituted with 1, 2, or 3 substituents, or with 1 or 2         substituents, selected from halo, cyano, C₁₋₆alkyl,         Het-C₁₋₆alkyl, Ar¹—C₁₋₆alkyl, cyanoC₁₋₆alkyl, C₂₋₆alkenyl,         cyano-C₂₋₆alkenyl, R^(6b)—O—C₃₋₆alkenyl, C₂₋₆alkynyl,         cyanoC₂₋₆alkynyl, R^(6b)—O—C₃₋₆alkyl, Ar¹, Het, R^(6b)—O—,         R^(6b)—S—, R^(6c)—SO—, R^(6c)—SO₂—, R^(6b)—O—C₁₋₆alkyl-SO₂—,         —N(R^(6a)R^(6b)), CF₃, R^(6c)—C(═O)—, R^(6b)—O—C(═O)—,         N(R^(6a)R^(6b))—C(═O)—, R^(6b)—O—C₁₋₆alkyl, R^(6b)—S—C₁₋₆alkyl,         R^(6c)—S(═O)₂—C₁₋₆alkyl, N(R^(6a)R^(6b))—C₁₋₆alkyl,         R^(6c)—C(═O)—C₁₋₆alkyl, R^(6b)—O—C(═O)—C₁₋₆alkyl,         N(R^(6a)R^(6b))—C(═O)—C₁₋₆alkyl, R^(6c)—C(═O)—NR^(6b),         H₂N—C(═NH)—;     -   (c) Ar² is phenyl, phenyl annelated with C₅₋₇cycloalkyl, or         phenyl substituted with 1, 2, or 3, or with 1 or 2, substituents         selected from halo, cyano, C₁₋₆alkyl, Het-C₁₋₆alkyl,         Ar¹—C₁₋₆alkyl, cyanoC₁₋₆alkyl, C₂₋₆alkenyl, cyanoC₂₋₆alkenyl,         R^(6b)—O—C₃₋₆alkenyl, C₂₋₆alkynyl, cyanoC₂₋₆alkynyl,         R^(6b)—O—C₃₋₆alkynyl, Ar¹, Het, R^(6b)—O—, R^(6b)—S—,         R^(6c)—SO₂—, —N(R^(6a)R^(6b)), CF₃, R^(6b)—O—C(═O)—,         N(R^(6a)R^(6b))—C(═O)—, R^(6b)—O—C₁₋₆alkyl, R^(6b)—S—C₁₋₆alkyl,         R^(6c)—S(═O)₂—C₁₋₆alkyl, N(R^(6a)R^(6b))—C₁₋₆alkyl,         R^(6c)—C(═O)—C₁₋₆alkyl, R^(6b)—O—C(═O)—C₁₋₆alkyl,         N(R^(6a)R^(6b))—C(═O)—C₁₋₆alkyl, R^(6c)—C(═O)—NR^(6b)—;     -   (d) Ar² is phenyl, phenyl annelated with C₅₋₇cycloalkyl, or         phenyl substituted with 1, 2, or 3, or with 1 or 2, substituents         selected from C₁₋₆alkyl, Het-C₁₋₆alkyl, Ar¹—C₁₋₆alkyl,         cyanoC₁₋₆alkyl, C₂₋₆alkenyl, cyanoC₂₋₆alkenyl,         R^(6b)—O—C₃₋₆alkenyl, C₂₋₆alkynyl, cyanoC₂₋₆alkynyl,         R^(6b)—O—C₃₋₆alkynyl, R^(6b)—O—C₁₋₆alkyl, R^(6b)—S—C₁₋₆alkyl,         R^(6c)—S(═O)₂—C₁₋₆alkyl, N(R^(6a)R^(6b))—C₁₋₆alkyl,         R^(6b)—O—C(═O)—C₁₋₆alkyl, N(R^(6a)R^(6b))—C(═O)—C₁₋₆alkyl;     -   (e) Ar² is phenyl, or phenyl substituted with 1, 2, or 3         substituents, or with 1 or 2 substituents, selected from         C₁₋₆alkyl, Het-C₁₋₆alkyl, Ar¹—C₁₋₆alkyl, cyanoC₁₋₆alkyl,         C₂₋₆alkenyl, cyanoC₂₋₆alkenyl, hydroxy-C₃₋₆alkenyl, C₂₋₆alkynyl,         cyanoC₂₋₆alkynyl, hydroxy-C₃₋₆alkynyl, R^(6b)—O—C₁₋₆alkyl,         amino-S(═O)₂—C₁₋₆alkyl, N(R^(6a)R^(6b))—C₁₋₆alkyl,         R^(6b)—O—C(═O)—C₁₋₆alkyl, amino-C(═O)—C₁₋₆alkyl, mono- and         di-C₁₋₆alkyl amino-C(═O)—C₁₋₆alkyl;     -   (f) Ar² is phenyl, or phenyl substituted with 1, 2, or 3         substituents or with 1 or 2 substituents selected from         C₁₋₆alkyl, Het-C₁₋₆alkyl, Ar¹—C₁₋₆alkyl, cyanoC₁₋₆alkyl,         C₂₋₆alkenyl, cyanoC₂₋₆alkenyl, C₂₋₆alkynyl, cyanoC₂₋₆alkynyl,         R^(6b)—O—C₁₋₆alkyl, amino-S(═O)₂—C₁₋₆alkyl,         R^(6b)—O—C(═O)—C₁₋₆alkyl, amino-C(═O)—C₁₋₆alkyl, mono- and         di-C₁₋₆alkylamino-C(═O)—C₁₋₆alkyl;     -   (g) Ar² is phenyl, or phenyl substituted with 1, 2, or 3         substituents or with 1 or 2 substituents selected from         C₁₋₆alkyl, R^(6b)—O—C₁₋₆alkyl and amino-C(═O)—C₁₋₆alkyl; or         selected from C₁₋₆alkyl, hydroxy-C₁₋₆alkyl and         amino-C(═O)—C₁₋₆alkyl.

The limitations in the substitutions on Ar² as specified under (a)-(g) above preferably apply to any Ar² being part of a radical R^(2a) or R^(3a) being C₁₋₆alkyl substituted with a radical —NR^(4a)R^(4b) wherein R^(4a) and/or R^(4b) is or are a radical Ar².

Other subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein

-   -   (h) Ar² is phenyl substituted with C₁₋₆alkyl, Het-C₁₋₆alkyl,         Ar¹—C₁₋₆alkyl, cyanoC₁₋₆alkyl, C₂₋₆alkenyl, cyanoC₂₋₆alkenyl,         C₂₋₆alkynyl, cyanoC₂₋₆alkynyl, R^(6b)—O—C₁₋₆alkyl,         amino-S(═O)₂—C₁₋₆alkyl, R^(6b)—O—C(═O)—C₁₋₆alkyl,         amino-C(═O)—C₁₋₆alkyl, mono- and         di-C₁₋₆alkylamino-C(═O)—C₁₋₆alkyl; and optionally further         substituted with one or with two of the substituents of Ar²         mentioned above in restrictions (a) to (g); or     -   (i) Ar² is phenyl substituted with R^(6b)—O—C₁₋₆alkyl,         amino-C(═O)—C₁₋₆alkyl; or phenyl substituted with         hydroxy-C₁₋₆alkyl, amino-C(═O)—C₁₋₆alkyl; and optionally further         substituted with one or with two of the substituents on Ar²         mentioned above in restrictions (a) to (g).

The limitations in the substitutions on Ar² as specified under (h)-(i) above preferably apply to any Ar² being part of a radical R^(2a) or R^(3a) being C₁₋₆alkyl substituted with a radical Ar².

Further subgroups are compounds of formula (I) or of any of the subgroups of compounds of formula (I) wherein:

-   -   (a) R^(6a) in particular is hydrogen, C₁₋₆alkyl, Ar¹,         Ar¹C₁₋₆alkyl, C₁₋₆alkylcarbonyl, Ar¹carbonyl,         Ar¹C₁₋₆alkylcarbonyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminoC₁₋₆alkyl,         mono- or di(C₁₋₆alkyl)aminoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,         (carboxyl)-C₁₋₆alkyl, (C₁₋₆alkyl-oxycarbonyl)-C₁₋₆alkyl,         aminocarbonylC₁₋₆alkyl, mono- and         di(C₁₋₆alkyl)amino-carbonylC₁₋₆alkyl, aminosulfonyl-C₁₋₆alkyl,         mono- and di(C₁₋₆alkyl)aminosulfonyl-C₁₋₆alkyl, Het,         Het-C₁₋₆alkyl, Het-carbonyl, Het-C₁₋₆alkylcarbonyl;     -   (b) R^(6a) more in particular is hydrogen, C₁₋₆alkyl, Ar¹,         Ar¹C₁₋₆alkyl, C₁₋₆alkyloxy-C₁₋₆alkyl, aminoC₁₋₆alkyl, mono- or         di(C₁₋₆alkyl)aminoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,         (carboxyl)-C₁₋₆alkyl, (C₁₋₆alkyloxycarbonyl)-C₁₋₆alkyl,         aminocarbonylC₁₋₆alkyl, mono- and         di(C₁₋₆alkyl)aminocarbonylC₁₋₆alkyl, aminosulfonyl-C₁₋₆alkyl,         mono- and di(C₁₋₆alkyl)aminosulfonyl-C₁₋₆alkyl, Het,         Het-C₁₋₆alkyl;     -   (c) R^(6a) further in particular is hydrogen, C₁₋₆alkyl,         Ar¹C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono- or         di(C₁₋₆alkyl)aminoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,         (carboxyl)-C₁₋₆alkyl, (C₁₋₆alkyloxycarbonyl)-C₁₋₆alkyl,         aminocarbonylC₁₋₆alkyl, mono- and         di(C₁₋₆alkyl)aminocarbonylC₁₋₆alkyl, aminosulfonyl-C₁₋₆alkyl,         mono- and di(C₁₋₆alkyl)aminosulfonyl-C₁₋₆alkyl, Het-C₁₋₆alkyl;     -   (d) R^(6a) further in particular is hydrogen, C₁₋₆alkyl,         Ar¹C₁₋₆alkyl, aminoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,         (carboxyl)-C₁₋₆alkyl, aminocarbonylC₁₋₆alkyl,         aminosulfonyl-C₁₋₆alkyl, morpholinyl-C₁₋₆alkyl; (e) R^(6a)         further in particular is hydrogen, hydroxyC₁₋₆alkyl,         aminocarbonylC₁₋₆alkyl, aminosulfonyl-C₁₋₆alkyl; or wherein     -   (e) R^(6a) is hydrogen, C₁₋₆alkyl, Ar¹ or Ar¹C₁₋₆alkyl; or         R^(6a) is hydrogen or C₁₋₆alkyl; or R^(6a) is hydrogen.

Further subgroups are compounds of formula (I) or of any of the subgroups of compounds of formula (I) wherein:

-   -   (f) R^(6b) preferably is hydrogen or C₁₋₆alkyl; or more         preferably is hydrogen;     -   (g) R^(6b) preferably is C₁₋₆alkyl.

In the group of compounds of formula (I) or in any of the subgroups of compounds of formula (I):

-   -   (a) Ar¹ preferably is phenyl or phenyl substituted with up to 3         substituents, or with up to 2 substituents, or with one         substituent, selected from halo, hydroxy, C₁₋₆alkyl,         hydroxyC₁₋₆alkyl, trifluormethyl, and C₁₋₆alkyloxy;     -   (b) Ar¹ more preferably is phenyl or phenyl substituted with up         to 3 substituents, or with up to 2 substituents, or with one         substituent, selected from halo, hydroxy, C₁₋₆alkyl and         C₁₋₆alkyloxy;     -   (c) Ar¹ more preferably is phenyl or phenyl substituted with up         to 3 substituents, or with up to 2 substituents, or with one         substituent, selected from halo and C₁₋₆alkyl.

Other subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein

-   -   (a) Het is tetrahydrofuranyl, furanyl, thienyl, thiazolyl,         oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl,         piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, pyridyl,         pyrazinyl, pyrimidinyl, tetrahydroquinolinyl, quinolinyl,         isoquinolinyl, benzodioxanyl, benzodioxolyl, indolinyl, indolyl,         which may optionally be substituted with oxo, amino, Ar¹,         C₁₋₄alkyl, aminoC₁₋₄alkyl, Ar¹C₁₋₄alkyl, mono- or         di(C₁₋₆alkyl)aminoC₁₋₆alkyl, mono- or di(C₁₋₆alkyl)amino,         (hydroxyC₁₋₆alkyl)amino, and optionally further with one or two         C₁₋₄alkyl radicals; or     -   (b) Het is tetrahydrofuranyl, furanyl, thienyl, thiazolyl,         oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, piperidinyl,         homopiperidinyl, piperazinyl, morpholinyl, pyridyl, pyrazinyl,         pyrimidinyl, tetrahydroquinolinyl, quinolinyl, isoquinolinyl,         benzodioxanyl, benzodioxolyl, indolinyl, indolyl, which may         optionally be substituted with oxo, amino, Ar¹, C₁₋₄alkyl,         aminoC₁₋₄alkyl, and optionally further with one or two C₁₋₄alkyl         radicals; or     -   (c) Het is furanyl, thienyl, pyrazolyl isoxazolyl, morpholinyl,         pyrimidinyl, quinolinyl, indolinyl, which may optionally be         substituted with one or two C₁₋₄alkyl radicals.     -   (d) Het is morpholinyl, which may optionally be substituted with         one or two C₁₋₄alkyl radicals; or     -   (d) Het is morpholinyl.

A particular embodiment of the present invention concerns compounds of formula (I) wherein Q, G, R¹ and R⁵ are as specified above in the definition of formula (I) or as in any of the subgroups of compounds of formula (I) specified herein; and wherein

-   -   (a) one of R^(2a) and R^(3a) is selected from —N(R^(4a)R^(4b)),         (R^(4a)R^(4b))N—CO—, C₁₋₆alkyl substituted with one or two         substituents selected from hydroxy, cyano, Ar², Het or         —N(R^(4a)R^(4b)) and C₂₋₆alkenyl substituted with cyano or Ar²;         and the other one of R^(2a) and R^(3a) is hydrogen; or     -   (b) one of R^(2a) and R^(3a) is selected from —N(R^(4a)R^(4b));         (R^(4a)R^(4b))N—CO—; C₁₋₆alkyl optionally substituted with         hydroxy, cyano, Ar², Het or —N(R^(4a)R^(4b)); C₁₋₆alkyl         substituted with hydroxy and Ar²; and C₂₋₆alkenyl substituted         with cyano or Ar²; and the other one of R^(2a) and R^(3a) is         hydrogen; or     -   (c) one of R^(2a) and R^(3a) is selected from         (R^(4a)R^(4b))N—CO—; C₁₋₆alkyl optionally substituted with         hydroxy, Ar², Het or —N(R^(4a)R^(4b)); and C₂₋₆alkenyl         substituted with Ar²; and the other one of R^(2a) and R^(3a) is         hydrogen; and     -   in case R^(2a) is different from hydrogen then R^(2b) is         hydrogen, C₁₋₆alkyl or halogen and R^(3b) is hydrogen;     -   in case R^(3a) is different from hydrogen then R^(3b) is         hydrogen, C₁₋₆alkyl or halogen and R^(2b) is hydrogen;     -   Ar², Het, R^(4a) and R^(4b) are as in the definitions of the         compounds of formula (I) or as in any subgroup specified herein.

Another particular embodiment of the present invention concerns compounds of formula (I) wherein Q, G, R¹ and R⁵ are as specified above in the definition of formula (I) or as in any of the subgroups of compounds of formula (I) specified herein; and

-   -   (d) one of R^(2a) and R^(3a) is selected from         (R^(4a)R^(4b))N—CO—; C₁₋₆alkyl optionally substituted with         hydroxy, Ar², Het or —N(R^(4a)R^(4b)); and C₂₋₆alkenyl         substituted with Ar¹; and the other one of R^(2a) and R^(3a) is         hydrogen; or     -   (e) one of R^(2a) and R^(3a) is selected from (R^(4a))HN—CO—;         C₁₋₆alkyl optionally substituted with hydroxy, Ar², Het,         —NH(R^(4a)) or —N(R^(4a)) Ar²; and C₂₋₆alkenyl substituted with         Ar¹; and the other one of R^(2a) and R^(3a) is hydrogen; or     -   (f) one of R^(2a) and R^(3a) is C₁₋₆alkyl optionally substituted         with hydroxy, Ar², Het, —NH(R^(4a)) or —N(R^(4a)) Ar²; and the         other one of R^(2a) and R^(3a) is hydrogen; or     -   (g) one of R^(2a) and R^(3a) is C₁₋₆alkyl optionally substituted         with hydroxy, Ar², —NH(R^(4a)) or —N(R^(4a)) Ar²; and the other         one of R^(2a) and R^(3a) is hydrogen;     -   (h) one of R^(2a) and R^(3a) is C₁₋₆alkyl optionally substituted         with —NH(R^(4a)) or —N(R^(4a))Ar²; and the other one of R^(2a)         and R^(3a) is hydrogen;     -   (i) one of R^(2a) and R^(3a) is C₁₋₆alkyl optionally substituted         with —NH(R^(4a)); and the other one of R^(2a) and R^(3a) is         hydrogen;     -   (j) one of R^(2a) and R^(3a) is C₁₋₆alkyl optionally substituted         with —N(R^(4a)) Ar²; and the other one of R^(2a) and R^(3a) is         hydrogen;         in case R^(2a) is different from hydrogen then R^(2b) is         hydrogen or C₁₋₆alkyl and R^(3b) is hydrogen;         in case R^(3a) is different from hydrogen then R^(3b) is         hydrogen or C₁₋₆alkyl and R^(2b) is hydrogen;     -   Ar², Het, R^(4a) and R^(4b) are as in the definitions of the         compounds of formula (I) or as in any subgroup specified herein.

Another particular embodiment of the present invention concerns compounds of formula (I) wherein Q, G, R¹ and R⁵ are as specified above in the definition of formula (I) or as in any of the subgroups of compounds of formula (I) specified herein; wherein R^(2a) and R^(3a) are as defined in (a)-(j) above and R^(2b) and R^(3b) are both hydrogen.

Another embodiment of the present invention concerns compounds of formula (I) wherein Q, G, R¹ and R⁵ are as specified above in the definition of formula (I) or as in any of the subgroups of compounds of formula (I) specified herein; wherein (k) one of R^(2a) and R^(3a) is C₁₋₆alkyl; and the other one of R^(2a) and R^(3a) is hydrogen; in case R^(2a) is different from hydrogen then R^(2b) is C₁₋₆alkyl and R^(3b) is hydrogen; in case R^(3a) is different from hydrogen then R^(3b) is C₁₋₆alkyl and R^(2b) is hydrogen.

Still another embodiment of the present invention concerns compounds of formula (I) wherein Q, G, R¹ and R⁵ are as specified above in the definition of formula (I) or as in any of the subgroups of compounds of formula (I) specified herein; wherein

-   -   one of R^(2a) and R^(3a) is selected from C₁₋₆alkyl substituted         with —N(R^(4a)R^(4b)), wherein R^(4b) is hydrogen;     -   and the other one of R^(2a) and R^(3a) is hydrogen; and     -   in case R^(2a) is different from hydrogen then R^(2b) is         hydrogen and R^(3b) is hydrogen;     -   in case R^(3a) is different from hydrogen then R^(3b) is         hydrogen and R^(2b) is hydrogen.

Still another embodiment of the present invention concerns compounds of formula (I) wherein Q, G, R¹ and R⁵ are as specified above or as in any of the subgroups of compounds specified herein; and

-   -   one of R^(2a) and R^(3a) is selected from C₁₋₆alkyl substituted         with —N(R^(4a)R^(4b)); and the other one of R^(2a) and R^(3a) is         hydrogen; and     -   in case R^(2a) is different from hydrogen then R^(2b) is         hydrogen and R^(3b) is hydrogen;     -   in case R^(3a) is different from hydrogen then R^(3b) is         hydrogen and R^(2b) is hydrogen; and further wherein     -   R^(4a) is Ar² and     -   R^(4b) is C₁₋₆alkyl, Ar²C₁₋₆alkyl, C₁₋₆alkyloxyC₁₋₆alkyl,         hydroxyC₁₋₆alkyloxyC₁₋₆alkyl, Ar¹C₁₋₆alkyloxyC₁₋₆alkyl,         (C₁₋₆alkyloxy)(hydroxy)C₁₋₆alkyl,         (Ar¹C₁₋₆alkyloxy)(hydroxy)C₁₋₆alkyl, aminoC₁₋₆alkyl, mono- and         di(C₁₋₆alkyl)aminoC₁₋₆alkyl, hydroxy-C₁₋₆alkyl,         aminocarbonylC₁₋₆alkyl, mono- and         di(C₁₋₆alkyl)aminocarbonylC₁₋₆alkyl,         C₁₋₄alkyloxycarbonylC₁₋₆alkyl, hydroxycarbonylC₁₋₆alkyl, Het or         Het-C₁₋₆alkyl.

Preferred compounds are those compounds listed in tables 1 through 13, more in particular the compound numbers 1 to 128, 131 to 153, 161 to 164, 171 to 182, 185, and 192 to 293.

Most preferred are:

-   -   compound 3 in Table 1, exemplified in example 11, the name of         which is         2-[6-{[2-(3-hydroxy-propyl)-5-methyl-phenylamino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol,     -   compound 58, in Table 2, exemplified in example 14, the name of         which is         2-[6-{[(3,5-dimethyl-phenyl)-(2-hydroxy-ethyl)-amino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol,     -   compound 59, in Table 2 the name of which is 2,         2-[6-{[(3,5-dimethyl-phenyl)-(3-aminocarbonyl-propyl)-amino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol

as well as the prodrugs, N-oxides, addition salts, quaternary amines and metal complexes thereof, in particular said three compounds and the acid-addition salts thereof.

The compounds of formula (I) or any of the subgroups thereof can be prepared as in the following reaction schemes.

In this scheme Q, G, R¹, R^(2a), R^(2b), R^(3a), R^(3b), R⁵ have the meanings defined above for the compounds of formula (I) or of any of the subgroups thereof. W is an appropriate leaving group, preferably it is chloro or bromo. The reaction of this scheme is typically conducted in a suitable solvent such as an ether, e.g. THF, a halogenated hydrocarbon, e.g. dichoromethane, CHCl₃, toluene, a polar aprotic solvent such as DMF, DMSO, DMA and the like. A base may be added to pick up the acid that is liberated during the reaction. If desired, certain catalysts such as iodide salts (e.g. KI) maybe added.

Compounds of formula (I) may be converted into each other following art-known functional group transformation reactions, comprising those described hereinafter.

Compounds of formula (I) wherein R^(2a) or R^(3a) is C₁₋₆alkoxycarbonyl or C₁₋₆alkyl substituted with C₁₋₆alkoxycarbonyl can be reduced, e.g. with LiAlH₄, to the corresponding compounds wherein R^(2a) or R^(3a) is hydroxy C₁₋₆alkyl. The latter group can be oxidized to an aldehyde group, e.g. with MnO₂, which can further be derivatized with amines, e.g. with a reductive amination process, to the corresponding C₁₋₆alkylamines or derivatized amines. Alternatively the compounds of formula (I) wherein R^(2a) or R^(3a) is hydroxyC₁₋₆alkyl can be converted to the corresponding haloC₁₋₆alkyl compounds, e.g. by treatment with a suitable halogenating agent such as SOCl₂ or POCl₃, which compounds subsequently are reacted with an amine or amine derivative.

These reactions can be represented in the following reaction schemes wherein a compound (I-1-a) or (I-1-b) is reduced to obtain a compound (I-2-a) or (I-2-b) and subsequently the alcohol group in (I-2-a) or (I-2-b) is oxidized with a mild oxidant to obtain an intermediate (I-3-a) or (I-3-b) and subsequently (I-3-a) or (I-3-b) are alkylated to obtain (I-4-a) or (I-4-b), which is further alkylated to obtain (I-5-a) or (I-5-b), wherein R¹² is C₁₋₆alkyl wherein is R^(4a) and R^(4b) are as defined in this specification and claims but are other than hydrogen:

In the following schemes the alcohol group in (I-2-a) or (I-2-b) is converted to a leaving group and subsequently the thus obtained products are reacted with an amine thus obtaining (I-6-a) or (I-6-b):

Compounds of formula (I) wherein R^(2a) or R^(3a) is an aldehyde can be converted to the corresponding compounds wherein R^(2a) or R^(3a) is C₂₋₆alkenyl or substituted C₂₋₆alkenyl by a Wittig reaction or a Wittig-Horner reaction. In the former instance a Wittig type reagent is used, such as a triphenylphosphoniumylide in a suitable reaction-inert solvent such as an ether, staring from triphenylphosphine and a halo derivative. The Wittig-Horner reaction is performed using a phosphonate, such as e.g. a reagent of formula di(C₁₋₆alkyloxy)-P(═O)—CH₂—CH₂—CN in the presence of a base, preferably a strong base, in an aprotic organic solvent. Compounds wherein R^(2a) or R^(3a) is C₂₋₆alkenyl or substituted C₂₋₆alkenyl can be reduced to the corresponding saturated alkyls, e.g. with hydrogen in the presence of a suitable catalyst such as Raney Ni.

These reactions can be represented in the following reaction schemes wherein an intermediate (I-3-a) or (I-3-b) is converted to a compound (I-7-a) or (I-7-b) using a Wittig or Wittig-Horner procedure; the double bond in (I-7-a) or (I-7-b) is selectively reduced thus obtaining compounds (I-8-a) or (I-8-b); the cyano group in (I-9-a) or (I-9-b) is reduced to a methylene-amine group thus obtaining compounds (I-10-a) or (I-10-b); the latter are mono- or dialkylated the latter thus obtaining compounds (I-11-a) or (I-11-b); or (I-12-a) or (I-12-b), wherein Alk¹ is C₄₋₆alkanediyl, R^(2a-1) is any of the substituents on alkenyl as defined in this specification and claims, and preferably wherein R^(2a-1) is Ar² or CN:

Compounds of formula (I) wherein R^(2a) or R^(3a) is an aldehyde can also be derivatized with a Grignard type of reaction to introduce aryl or alkyl groups.

Nitro groups can be reduced to amino groups, which subsequently may be alkylated to mono- or dialkylamino groups, or acylated to arylcarbonylamino or alkylcarbonyl-amino and the like groups. Cyano groups may be reduced to aminomethylene groups, which similarly may be derivatized.

A number of the intermediates used to prepare the compounds of formula (I) are known compounds or are analogs of known compounds which can be prepared following modifications of art-known methodologies readily accessible to the skilled person. A number of preparations of intermediates are given hereafter in somewhat more detail.

In a first step, a diaminobenzene (IV) is cyclized with urea in a suitable solvent, e.g. xylene, to yield a benzimidazolone (V). The latter is converted to a benzimidazole derivative (V) wherein W is a leaving group as specified above, in particular by reaction of (V) with a suitable halogenating agent, for example POCl₃, and the resulting intermediate (VI) is reacted with the amine derivative (VII) to obtain intermediate (II).

The compounds of formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t.butyl hydro-peroxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.

Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g., counter-current distribution, liquid chromatography and the like.

The compounds of formula (I) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) which are sufficiently basic or acidic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali or acid. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure staring materials.

In a further aspect, the present invention concerns a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as specified herein, or a compound of any of the subgroups of compounds of formula (I) as specified herein, and a pharmaceutically acceptable carrier. A therapeutically effective amount in this context is an amount sufficient to prophylaxictically act against, to stabilize or to reduce viral infection, and in particular RSV viral infection, in infected subjects or subjects being at risk of being infected. In still a further aspect, this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound of formula (I), as specified herein, or of a compound of any of the subgroups of compounds of formula (I) as specified herein.

Therefore, the compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form or metal complex, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.

The compounds of the present invention may also be administered via oral inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder, a solution being preferred. Any system developed for the delivery of solutions, suspensions or dry powders via oral inhalation or insufflation are suitable for the administration of the present compounds.

Thus, the present invention also provides a pharmaceutical composition adapted for administration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Preferably, the compounds of the present invention are administered via inhalation of a solution in nebulized or aerosolized doses.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.

The compounds of formula (I) show antiviral properties. Viral infections treatable using the compounds and methods of the present invention include those infections brought on by ortho- and paramyxoviruses and in particular by human and bovine respiratory syncytial virus (RSV). A number of the compounds of this invention moreover are active against mutated strains of RSV. Additionally, many of the compounds of this invention show a favorable pharmacokinetic profile and have attractive properties in terms of bioavailabilty, including an acceptable half-life, AUC and peak values and lacking unfavourable phenomena such as insufficient quick onset and tissue retention.

The in vitro antiviral activity against RSV of the present compounds was tested in a test as described in the experimental part of the description, and may also be demonstrated in a virus yield reduction assay. The in vivo antiviral activity against RSV of the present compounds may be demonstrated in a test model using cotton rats as described in Wyde et al. (Antiviral Research (1998), 38, 31-42).

Due to their antiviral properties, particularly their anti-RSV properties, the compounds of formula (I) or any subgroup thereof, their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms, are useful in the treatment of individuals experiencing a viral infection, particularly a RSV infection, and for the prophylaxis of these infections. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses, in particular the respiratory syncytial virus.

The compounds of the present invention or any subgroup thereof may therefore be used as medicines. Said use as a medicine or method of treatment comprises the systemic administration to viral infected subjects or to subjects susceptible to viral infections of an amount effective to combat the conditions associated with the viral infection, in particular the RSV infection.

The present invention also relates to the use of the present compounds or any subgroup thereof in the manufacture of a medicament for the treatment or the prevention of viral infections, particularly RSV infection.

The present invention furthermore relates to a method of treating a warm-blooded animal infected by a virus, or being at risk of infection by a virus, in particular by RSV, said method comprising the administration of an anti-virally effective amount of a compound of formula (I), as specified herein, or of a compound of any of the subgroups of compounds of formula (I), as specified herein.

In general it is contemplated that an antivirally effective daily amount would be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be thing, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.

Also, the combination of another antiviral agent and a compound of formula (I) can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of formula (I), and (b) another antiviral compound, as a combined preparation for simultaneous, separate or sequential use in antiviral treatment. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. For instance, the compounds of the present invention may be combined with interferon-beta or tumor necrosis factor-alpha in order to treat or prevent RSV infections.

EXAMPLES

The following examples are intended to illustrate the present invention and not to limit it thereto.

The terms ‘compound 58, compound 143, etc. used in these examples refers to the same compounds in the tables.

The compounds were analyzed by LC/MS using the following equipment:

-   -   LCT: electrospray ionisation in positive mode, scanning mode         from 100 to 900 amu; Xterra MS C18 (Waters, Milford, Mass.) 5         μm, 3.9×150 mm); flow rate 1 ml/min. Two mobile phases (mobile         phase A: 85% 6.5 mM ammonium acetate+15% acetonitrile; mobile         phase B: 20% 6.5 mM ammonium acetate+80% acetonitrile) were         employed to run a gradient from 100% A for 3 min to 100% B in 5         min., 100% B for 6 min to 100% A in 3 min, and equilibrate again         with 100% A for 3 min).     -   ZQ: electrospray ionisation in both positive and negative         (pulsed) mode scanning from 100 to 1000 amu; Xterra RP C18         (Waters, Milford, Mass.) 5 μm, 3.9×150 mm); flow rate 1 ml/min.         Two mobile phases (mobile phase A: 85% 6.5 mM ammonium         acetate+15% acetonitrile; mobile phase B: 20% 6.5 mM ammonium         acetate+80% acetonitrile) were employed to run a gradient         condition from 100% A for 3 min to 100% B in 5 min., 100% B for         6 min to 100% A in 3 min, and equilibrate again with 100% A for         3 min).

Example 1

A mixture of 3,4-diamino benzoic acid ethyl ester (0.166 mol) and urea (0.199 mol) in xylene (300 ml) was stirred under reflux for 12 hours. The reaction was cooled down to room temperature. The precipitate was filtered off, rinsed with xylene and diisopropylether, and then dried, yielding 32 g of intermediate a-1 (93%, melting point: >260° C.).

A mixture of a-1 (0.073 mol) in POCl₃ (150 ml) was stirred at 100° C. HCl conc. (around 1.5 ml) was added drop wise very carefully until the dissolution of a-1. The mixture was stirred at 120° C. for 6 hours. The solvent was evaporated until dryness. The residue was takenup in H₂O/ice, basified with K₂CO₃ (powder) and extracted with ethylacetate+10% methanol. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness, yielding 13.5 g of intermediate a-2 (83%, melting point: 178° C.).

A mixture of a-2 (0.0356 mol) and N-propylamino-morpholine (0.0427 mol) was stirred at 120° C. for 4 hours, and then taken up in CH₂Cl₂/CH₃OH. The organic layer was washed with a 10% solution of K₂CO₃ in water, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (11.9 g) was purified by column chromatography over silica gel (eluent CH₂Cl₂/CH₃OH/NH₄OH 94/6/0.2; 15-40 μm). The pure fractions were collected and the solvent was evaporated, yielding 6 g of intermediate a-3 (47%).

A mixture of a-3 (0.018 mol), a-4 (0.027 mol) and K₂CO₃ (0.054 mol) in CH₃CN (100 ml) and dimethylformamide (10 ml) was stirred at 80° C. for 12 hours. The solvent was evaporated until dryness. The residue was taken up in CH₂Cl₂/H₂O. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue was crystallized from 2-propanone. The precipitate was filtered, washed with H₂O and dried, yielding 2.8 g of intermediate a-6 (34%, melting point: 176° C.). The mother layer was evaporated until dryness and purified by chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 93/7/0.7; 15-40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH₃CN/diisopropylether, yielding 1.6 g of intermediate a-5 (20%, melting point: 184° C.).

A mixture of a-5 (0.0035 mol) in tetrahydrofuran (60 ml) was cooled down to 5° C. under N₂ flow. LiAlH₄ (0.0105 mol) was added portion wise. The mixture was stirred at 5° C. for 1 hour, and then sired at room temperature for 2 hours. A minimum of H₂O was added. CH₂Cl₂ was added. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue was crystallized from 2-propanone/diisopropylether. The precipitate was filtered off and dried, yielding 1.2 g of intermediate a-7 (83%). Part of this fraction (0.1 g) was crystallized from 2-propanone/CH₃CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.074 g (melting point: 192° C.). Intermediate a-8 (melting point: 134° C.) was prepared in an analogous way.

A mixture of a-7 (0.0024 mol) and MnO₂ (2 g) in CH₂Cl₂ (50 ml) was stirred at room temperature for 12 hours, and then filtered over celite. Celite was washed with H₂O. The solvent of the filtrate was evaporated until dryness, yielding 0.9 g of intermediate a-9 (90%, melting point: 206° C.). Intermediate a-10 was prepared in an analogous way.

Example 2

LiAlH₄ (0.146 mol) was added portion wise to a solution of tetrahydrofuran (200 ml) at 5° C. under N₂ flow. A solution of b-1 (0.073 mol) in tetrahydrofuran (200 ml) was then added drop wise. The mixture was stirred at 5° C. for 3 hours. A minimum of H₂O was then added, followed by a solution of CH₂Cl₂/CH₃OH (90/10). The resulting mixture was dried (over MgSO₄), filtered and the solvent was evaporated until dryness, yielding 12.6 g of intermediate b-2 (95%, melting point: 179° C.).

A mixture of b-2 (0.069 mol) and N-propylamino-morpholine (0.207 mol) was stirred at 125° C. for 4 hours, and then taken up in CH₂Cl₂/CH₃OH. The organic layer was washed with a 10% solution of K₂CO₃ in water, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (37 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 90/10/0.5; 20-45 μm). The pure fractions were collected and the solvent was evaporated, yielding 16.5 g of intermediate b-3 (82%).

A mixture of b-3 (0.0396 mol), b-4 (0.0475 mol) and K₂CO₃ (0.1188 mol) in dimethylformamide (110 ml) was stirred at room temperature for 12 hours. The reaction was poured into ice/water. The aqueous layer was saturated with K₂CO₃ (powder) and extracted with a solution of CH₂Cl₂/CH₃OH (95/5). The residue was purified by chromatography over silica gel (eluent CH₂Cl₂/CH₃OH/NH₄OH 90/10/1; 20-45 μm). The pure fractions were collected and the solvent was evaporated, yielding 5.4 g of intermediate b-5 (33%, melting point: 192° C.) and 5 g of intermediate b-6 (31%, melting point: 134° C.).

SOCl₂ (0.81 ml) was added drop wise to a mixture of b-5 (0.0006 mol) in CH₂Cl₂ (10 ml) at 5° C. The mixture was stirred at 5° C. for 2 hours, then brought to room temperature and stirred for 12 hours. The solvent was evaporated until dryness, yielding 0.42 g of intermediate b-7 (100%).

Example 3

TiCl₃ (15% in H₂O) (0.026 mol) was added drop wise at 0° C. to a solution of c-1 (3-(4-Methyl-2-nitro-phenyl)-prop-2-en-1-ol, 0.0026 mol) in tetrahydrofuran (30 ml). The mixture was stirred at 0° C. for 30 minutes, then at room temperature for 12 hours, poured into H₂O and basified slowly at 0° C. with K₂CO₃. EtOAc was added. The mixture was filtered over celite. Celite was washed with EtOAc. The filtrate was decanted. The organic layer was washed with H₂O, dried (over MgSO₄), filtered, and the solvent was evaporated. The residue (0.4 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1). The pure fractions were collected and the solvent was evaporated Yield: 0.1 g of intermediate c-2 (3-(2-Amino-4-methyl-phenyl)-prop-2-en-1-ol, 24%).

Example 4

A mixture of d-1 (4-Methyl-2-nitro-phenol, 0.00653 mol), 2-bromo-ethanol (0.00653 mol) and K₂CO₃ (0.0131 mol) in CH₃CN (15 ml) was stirred under reflux for 6 hours and then cooled down to room temperature. The solution was concentrated. The residue was taken up in CH₂Cl₂ and washed with H₂O. The organic layer was separated, dried (over MgSO₄), filtered and concentrated. Yield: 1.3 g of intermediate d-2 (2-(4-Methyl-2-nitro-phenoxy)-ethanol, 1000%). The compound was used directly in the next reaction step.

A mixture of d-2 (2-(4-Methyl-2-nitro-phenoxy)-ethanol, 0.0066 mol) and Raney Nickel (1.3 g) in CH₃OH (30 ml) was hydrogenated under a 3 bar pressure at room temperature for 2 hours. The solution was filtered through a pad of celite. The pad was rinsed with CH₃OH and the filtrate was concentrated. The residue was taken up in CH₂Cl₂. The precipitate was filtered off and dried. Yield: 0.41 g of intermediate d-3 (2-(2-Amino-4-methyl-phenoxy)-ethanol, 37%, melting point: 135° C.).

Example 5

A mixture of e-1 (3-(4-Methyl-2-nitro-phenyl)-acrylic acid ethyl ester, 0.0063 mol) in a solution of NH₃/CH₃OH 7N (20 ml) was stirred at 80° C. for 24 hours, then cooled to room temperature and evaporated. The residue was taken up in CH₂Cl₂. The precipitate was filtered off and dried. Yield: 0.78 g of e-2 (3-(4-Methyl-2-nitro-phenyl)-acrylamide, 60%, melting point: 208° C.).

A mixture of e-2 (3-(4-Methyl-2-nitro-phenyl)-acrylamide, 0.0037 mol) and Raney Nickel (0.7 g) in CH₃OH (30 ml) was hydrogenated at room temperature for 2 hours, and then filtered over celite. Celite was washed with CH₃OH. The filtrate was evaporated. Yield: 0.7 g of e-3 (3-(2-Amino-4-methyl-phenyl)-propionamide, 100%).

Example 6

A mixture of f-1 (2-(4-Bromo-2-nitro-phenyl)-ethanol, 0.002 mol) and Raney Nickel (0.002 mol) in CH₃OH (20 ml) and thiophene (0.5 ml) was hydrogenated at room temperature for 1 hour under a 3 bar pressure, then filtered over celite. Celite was washed with CH₃OH. The filtrate was evaporated. Yield: 0.4 g of f-2 (2-(2-Amino-4-bromo-phenyl)-ethanol, 91%).

Tributyl-vinyl-stannane (0.0092 mol) was added drop wise at room temperature to a mixture of f-2 (2-(2-Amino-4-bromo-phenyl)-ethanol, 0.0046 mol) and Pd(PPh₃)₄ (0.0004 mol) in dioxane (20 ml) under N₂ flow. The mixture was stirred at 80° C. for 12 hours, poured into H₂O and extracted with Ethylacetate. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated. The residue (3.4 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 96/4/0.1; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.21 g of f-3 (2-(2-Amino-4-vinyl-phenyl)-ethanol, 28%).

Example 7

A mixture of g-1 (4-Bromo-1-methyl-2-nitro-benzene, 0.0104 mol), g-2 (3-thiopheneboronic acid, 0.0156 mol), Na₂CO₃ 2M in H₂O (30 ml) and Pd(PPh₃)₂Cl₂ (0.00104 mol) in dioxane (30 ml) was stirred under reflux for 2 hours. The reaction was cooled down to room temperature and ethylacetate was added. The organic layer was separated, washed with a saturated solution of NaCl, dried (over MgSO₄), filtered and the solvent was evaporated. Yield: 3.7 g of g-3 (3-(4-Methyl-3-nitro-phenyl)-thiophene, 100%). The crude compound was used directly in the next reaction step.

A mature of g-3 (3-(4-Methyl-3-nitro-phenyl)-thiophene, 0.00502 mol), paraformaldehyde (0.002 mol) and Triton B 40% in H₂O (0.11 ml) in DMSO (1.1 ml) was stirred at 90° C. for 3 hours. The crude solution was purified by column chromatography over silica gel (eluent: CH₂Cl₂). Yield: 0.44 g of g-4 (2-(2-Nitro-4-thiophen-3-yl-phenyl)-ethanol, 35%).

A mixture of g-4 (2-(2-Nitro-4-thiophen-3-yl-phenyl)-ethanol, 0.00176 mol) and Raney Nickel (0.4 g) in CH₃OH (40 ml) was hydrogenated at room temperature for 2 hours under a 3 bar pressure, then filtered over celite. Celite was washed with CH₃OH. The filtrate was evaporated. Yield: 0.37 g of g-5 (2-(2-Amino-4-thiophen-3-yl-phenyl)-ethanol, 96%).

Example 8

A mixture of h-1 (2-(4-Bromo-2-nitro-phenyl)-ethanol, 0.00205 mol), h-2 (furan-3-boronic acid, 0.00307 mol), Na₂CO₃ 2M in H₂O (7.5 ml) and Pd(PPh₃)₂Cl₂ (0.000205 mol) in dioxane (7.5 ml) was stirred under reflux for 3 hours. The reaction was cooled down to room temperature and ethylacetate was added. The organic layer was separated, washed with a saturated solution of NaCl, dried (over MgSO₄), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂). Yield: 0.8 g of h-3 (2-(4-Furan-3-yl-2-nitro-phenyl)-ethanol, 73%).

A mixture of h-3 (2-(4-Furan-3-yl-2-nitro-phenyl)-ethanol, 0.0015 mol) and Raney Nickel (0.3 g) in CH₃OH (30 ml) was hydrogenated at room temperature for 2 hours under a 3 bar pressure, then filtered over celite. Celite was washed with CH₃OH. The filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.2; 10 μm). Yield: 0.09 g of h-4 (2-(2-Amino-4-furan-3-yl-phenyl)-ethanol, 30%).

Example 9

A mixture of i-1 (1-Iodo-4-methyl-2-nitro-benzene, 0.0038 mol), methyl-vinylketone (0.0076 mol), Et₃N (0.0076 mol) and Pd(OAc)₂ (0.00019 mol) in CH₃CN (6 ml) were stirred in a microwave oven (100° C., 100 W) for 5 min. The reaction was then filtered through a pad of celite and the filtrate was concentrated. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/Cyclohexane 70/30). Yield: 0.65 g of i-2 (4-(4-Methyl-2-nitro-phenyl)-but-3-en-2-one, 78%, melting point: 58° C.).

NaBH₄ (0.00633 mol) was added drop wise to a solution of i-2 (4-(4-Methyl-2-nitro-phenyl)-but-3-en-2-one, 0.00316 mol) in CH₃OH (10 ml) at 0° C. The reaction was stirred at 0° C. for 1 hour and then poured on ice. The aqueous layer was extracted with ethylacetate. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated. Yield: 0.65 g of i-3 (4-(4-Methyl-2-nitro-phenyl)-but-3-en-2-ol, 1000%). The crude compound was used directly in the next reaction step.

A mixture of i-3 (4-(4-Methyl-2-nitro-phenyl)-but-3-en-2-ol, 0.00316 mol) and Raney Nickel (0.6 g) in CH₃OH (20 ml) was hydrogenated at room temperature for 2 hours under a 3 bar pressure, then filtered over celite. Celite was washed with CH₃OH. The filtrate was evaporated. Yield: 0.5 g of i-4 (4-(2-Amino-4-methyl-phenyl)-butan-2-ol, 88%).

Example 10

CH₃CO₂H (0.2 ml) was added at room temperature to a mixture of j-1 (0.0004 mol), 3,5-dimethyl-aniline (0.0005 mol) and NaBH₃CN (0.0005 mol) in CH₃CN (25 ml). The mixture was stirred at room temperature for 30 minutes. CH₃CO₂H (0.2 ml) was added. The mixture was stirred at room temperature for 12 hours. The solvent was evaporated until dryness. The residue was taken up in CH₂Cl₂. The organic layer was washed with a 10% solution of K₂CO₃ in water, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (0.24 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 90/10/0.2; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.15 g, 60%) was crystallized from 2-propanone/CH₃CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.121 g of 2-[6-[(3,5-dimethyl-phenylamino)-methyl]-2-(3-morpholin-4-yl-propylamino)-benzoimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol (example of j-2, compound 23, 48%, melting point: 199° C.).

Example 11

CH₃CO₂H (0.2 ml) was added at room temperature to a mixture of k-1 (0.0004 mol), 3-(2-amino-4-methyl-phenyl)-propan-1-ol (0.0005 mol) and BH₃CN— on solid support (0.0007 mol) in CH₃OH (20 ml). The mixture was stirred at room temperature for 12 hours. The solid support was filtered off, rinsed with CH₃OH and the filtrate was concentrated. The residue was taken up in a 10% solution of K₂CO₃ in water and extracted with CH₂Cl₂/CH₃OH (95/5). The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue was purified by colony chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 92/8/1; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone/diisopropylether. The precipitate was filtered off and dried, yielding 0.223 g of 2-[6-{[2-(3-Hydroxy-propyl)-5-methyl-phenylamino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzoimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol (example of k-2, compound 3, 82%, melting point: 208° C.).

Example 12

l-2 (0.0103 mol) was added drop wise to a mixture of l-1 (0.0051 mol), Pd(PPh₃)₂Cl₂ (0.0005 mol) and CuI (0.0005 mol) in Et₃N (15 ml) under N₂ flow. The mixture was stirred at room temperature for 4 hours, poured into H₂O and extracted with EtOAc. The organic layer was washed with H₂O, dried (over MgSO₄), filtered and the solvent was evaporated. The residue (2.1 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/cyclohexane 70/30). The pure fractions were collected and the solvent was evaporated. Yield: 1 g of intermediate l-3 (79%).

CH₃CO₂H (5 drops) then BH₃CN— on solid support (0.0009 mol) were added at room temperature to a mixture of l-4 (0.0004 mol) and l-3 (0.0007 mol) in CH₃OH (3 ml). The mixture was stirred at room temperature for 48 hours, then filtered and washed with CH₂Cl₂/CH₃OH. The filtrate was evaporated. Yield: 0.4 g of intermediate l-5 (100%). This product was used directly in the next reaction step.

A mixture of l-5 (0.0004 mol) and pyridinium p-toluene sulfonate (0.00004 mol) in EtOH (15 ml) was stirred at 60° C. for 12 hours. HCl 3N (5 drops) was added. The mixture was stirred at 60° C. for 3 hours, then cooled to room temperature and evaporated. The residue was taken up in CH₂Cl₂/CH₃OH. The organic layer was washed with K₂CO₃ 10%, dried (over MgSO₄), filtered and the solvent was evaporated. The residue (0.33 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 94/6/0.5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried Yield: 0.016 g of 2-[6-{[2-(3-Hydroxy-prop-1-ynyl)-5-methyl-phenylamino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzoimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol (l-6, compound 34, 6%, melting point: 225° C.).

Example 13

A mixture of m-1 (0.000347 mol), m-2 (0.00041 mol) and K₂CO₃ (0.00173 mol) in dimethylformamide (10 ml) was stirred at 80° C. for 3 hours. The reaction was cooled down to room temperature and was poured into a 10% solution of K₂CO₃ in water. The solution was saturated with K₂CO₃ (powder) and extracted with CH₂Cl₂/CH₃OH (95/5). The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (0.15 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.5; 10 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.03 g of intermediate m-3 (15%, mixture E/Z (89/11)).

A mixture of m-3 (0.000106 mol) and Pd/C 10% (0.020 g) in CH₃OH (15 ml) and tetrahydrofuran (15 ml) was hydrogenated at room temperature for 6 hours under a 3 bar pressure. The reaction was filtered over celite. The celite was rinsed and the filtrate was evaporated until dryness. The residue (0.06 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 93/7/0.5; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.028 g) was crystallized from 2-propanone/diisopropylether, yielding 0.021 g of 3-(4-{[3-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-3,5-dimethyl-phenyl)-propionitrile (m-4, compound 49, 35%, melting point: 114° C.).

The isomers substituted in position 5 on the benzimidazole moiety were synthesized analogous to the procedures described in schemes J and K, starting from intermediate a-10.

Example 14

(a) Synthesis of Anilines n-2:

A mixture of 3-bromo-aniline (0.037 mol), 2-bromo-ethanol (0.074 mol) and triethylamine (0.0555 mol) in toluene (35 ml) was stirred under reflux for 12 hours. The reaction was cooled down to room temperature and the precipitate was filtered off. The solvent of the filtrate was evaporated until dryness. The residue (22 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.1; 20-45 μm). The pure fractions were collected and the solvent was evaporated, yielding 4.8 g of 2-(3-bromo-phenylamino)-ethanol (60%).

5-(3,5-dimethyl-phenylamino)-pentanoic acid ethyl ester and 3-(3-bromo-phenylmino)-propionic acid ethyl ester and 4-m-tolylamino-butane-1-sulfonic acid amide and phosphoric acid 2-(3,5-dimethyl-phenylamino)-ethyl ester diethyl ester and [2-(3,5-dimethyl-phenylamino)-ethyl]-phosphonic acid diethyl ester and 4-m-tolylamino-butane-1-sulfonic acid methylamide were prepared analogously.

A mixture of 3,5-dimethyl-aniline (0.04 mol), 2-bromo-ethanol (0.033 mol) and K₂CO₃ (0.033 mol) in CH₃CN (50 ml) was stirred at 80° C. for 12 hours. The reaction was cooled down to room temperature and the solvent was evaporated. The residue was taken up in CH₂Cl₂/CH₃OH (95/5) and washed with a saturated solution of K₂CO₃ in water. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0.1; 20-45 μm). The pure fractions were collected and the solvent was evaporated, yielding 1.9 g of 2-(3,5-dimethyl-phenylamino)-ethanol (29%).

3-(3,5-dimethyl-phenylamino)-propionic acid ethyl ester and 4-(3,5-dimethyl-phenylamino)-butyric acid ethyl ester and (3,5-dimethyl-phenyl)-(2-morpholin-4-yl-ethyl)-amine and [2-(3,5-dimethyl-phenylamino)-ethyl]-carbamic acid tert-butyl ester were prepared analogously.

3-(3,5-dimethyl-phenylamino)-propionic acid ethyl ester (0.0026 mol) in a 7N solution of NH₃ in CH₃OH was stirred at 80° C. in a sealed vessel. The reaction was cooled down to room temperature and the solvent was evaporated until dryness, yielding 0.5 g of 3-(3,5-dimethyl-phenylamino)-propionamide (100%).

4-(3,5-dimethyl-phenylamino-butyramide and 4-m-tolylamino-butyramide and 3-m-tolylamino-propionamide and 3-(3-bromo-phenylamino)-propionamide were prepared analogously.

3-(3,5-dimethyl-phenylamino)-propionic acid ethyl ester (0.00226 mol) in tetrahydrofuran (5 ml) was added drop wise to a slurry of LiAlH₄ (0.0034 mol) in tetrahydrofuran (10 ml) at 5° C. under N₂ flow. The mixture was stirred at 5° C. for 1 hour. A minimum of water and CH₂Cl₂/CH₃OH (95/5) were added. The solution was dried (over MgSO₄), filtered and the solvent was evaporated until dryness, yielding 0.35 g of 3-(3,5-dimethyl-phenylamino-propan-1-ol (86%). 5-(3,5-dimethyl-phenylamino)-pentan-1-ol was prepared analogously.

A mixture of 3,5-Dimethyl-phenylamine (0.0289 mol), 1-Bromo-3-methyl-butan-2-one (0.0347 mol) and NEt₃ (0.0433 mol) in toluene (80 ml) was stirred at 120° C. for 24 hours. The precipitate was filtered. The filtrate was evaporated until dryness. The residue (6.3 g) was purified by column chromatography over silica gel (Cyclohexane/AcOEt 95/5; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.789 g of 1-(3,5-Dimethyl-phenylamino)-3-methyl-butan-2-one (13%).

NaBH₄ (0.0046 mol) was added portion wise at 5° C. to a solution of 1-(3,5-Dimethyl-phenylamino)-3-methyl-butan-2-one, 0.0038 mol) in tetrahydrofuran (10 ml) and CH₃OH (10 ml). The mixture was stirred at room temperature for 6 hours, poured into K₂CO₃ 10% and extracted with CH₂Cl₂. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 99/1/0.1; 20 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.25 g of 1-(3,5-Dimethyl-phenylamino)-3-methyl-butan-2-ol (52%, melting point: 65° C.).

A mixture of 3,5-Dimethyl-phenylamine (0.0422 mol) and 2-phenoxymethyl-oxirane (0.0422 mol) in EtOH (50 ml) was stirred at 80° C. for 12 hours, and then cooled to room temperature. The precipitate was filtered, washed with H₂O and dried. The mother layer was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂; 10 μm). Two fractions were collected and the solvent was evaporated Yield: 0.4 g of intermediate 1-(3,5-Dimethyl-phenylamino)-3-phenoxy-propan-2-ol (4%, melting point: 65° C.).

(b) Synthesis of Final Compounds n-4 and n-5:

A mixture of n-3 (0.000695 mol), 2-(3,5-dimethyl-phenylamino)-ethanol (0.0009 mol) and K₂CO₃ (0.0035 mol) in dimethylformamide (40 ml) was stirred at 80° C. for 4 hours. H₂O was added. The solution was saturated with K₂CO₃ (powder) and extracted with CH₂Cl₂/CH₃OH (95/5). The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated. The residue (0.5 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 93/7/0.5; 15-40 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.120 g of fraction 1 (31%) and 0.045 g of fraction 2 (12%). Fraction 1 was crystallized from CH₃CN/diisopropylether. The precipitate was filtered, rinsed with diisopropylether and dried, yielding 0.1 g of 2-[6-{[(3,5-ethyl-phenyl)-(2-hydroxy-ethyl)-amino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzoimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol (Compound 58, example of compound n-4; 26%, melting point: 180° C.). Fraction 2 was crystallized from 2-propanone/diisopropylether. The precipitate was filtered, rinsed with diisopropylether and dried, yielding 0.016 g of 2-[6-[4-(2-hydroxy-ethylamino)-2,6-dimethylbenzyl]-2-(3-morpholin-4-yl-propylamino)-benzoimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol (Compound 143, example of compound n-5, 4%, melting point: 162° C.).

A mixture of 4-{(3,5-dimethyl-phenyl)-[3-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-butyric acid ethyl ester (Compound 71), prepared as described for compounds n-4, (0.000175 mol) and LiOH/H₂O (0.00035 mol) in tetrahydrofuran (8 ml) and H₂O (8 ml) was stirred at room temperature for 12 hours. The tetrahydrofuran was evaporated and a 1N solution of NaOH in water was added. The solution was extracted with CH₂Cl₂/CH₃OH (95/5). The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated. The residue was taken up in H₂O. The precipitate was filtered off and dried, yielding 0.059 g of 4-{(3,5-dimethyl-phenyl)-[3-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-butyric acid (Compound 62, 56%, melting point: 121° C.).

A mixture of (2-{(3,5-dimethyl-phenyl)-[3-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-ethyl)-carbamic acid tert-butyl ester, prepared as described for compounds n-4, (0.00012 mol) in a 3N solution of HCl in water (10 ml) and tetrahydrofuran (10 ml) was stirred at room temperature for 12 hours. The precipitate was filtered off and taken up in a 10% solution of K₂CO₃ in water. The solution was saturated with K₂CO₃ (powder) and extracted with CH₂Cl₂/CH₃OH (95/5). The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (0.07 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 92/8/1; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH₃CN/CH₃OH/diisopropylether, yielding 0.03 g of 2-[6-{[(2-amino-ethyl)-(3,5-dimethyl-phenyl)-amino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzoimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol (Compound 66, 44%, melting point: 196° C.).

Example 15

A mixture of o-1 (0.0125 mol), o-2 (0.0145 mol) and Cs₂CO₃ (0.0605 mol) in dimethylformamide (300 ml) was stirred at 80° C. for 4 hours, poured into ice water and extracted with CH₂Cl₂. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated. The residue (11.3 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 93/7/0.5; 15-40 μm). The pure fictions were collected and the solvent was evaporated. Yield: 2.6 g (35%). This fraction was crystallized from 2-propanone/CH₃OH/Diisopropylether. The precipitate was filtered off and dried. Yield: 2.17 g of 4-{(3,5-Dimethyl-phenyl)-[3-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-butyramide (o-3, compound 59, 29%, melting point: 170° C.).

Example 16

A mixture of p-1 (0.0011 mol) and N-(propylamino)-morpholine (0.0044 mol) was stirred at 130° C. for 4 hours, then brought to room temperature, taken up in H₂O and extracted with CH₂Cl₂. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated. The residue (0.328 g) was purified by column chromatography over silica gel (eluent CH₂Cl₂/CH₃OH/triethylamine 99/1/0.1 to 90/10/1; 10 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.216 g of intermediate p-2 (68%).

A mixture of p-2 (0.0007 mol), p-3 (0.0008 mol) and K₂CO₃ (0.003 mol) in dimethylformamide (6 ml) was stirred at 70° C. for 12 hours, then brought to room temperature, taken up in H₂O and extracted with CH₂Cl₂. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated. The residue (0.5 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 93/710.5 then toluene/iPrOH/NH₄OH 80/20/1; 10 μm). Two fractions were collected and the solvent was evaporated, yielding 0.13 g of fraction 1 and 0.036 g of fraction 2. Fraction 1 was taken up in diisopropylether. The precipitate was filtered off and dried, yielding 0.1 g of 2-[4,6-dimethyl-2-(3-morpholin-4-yl-propylamino)-benzoimidazol-1-yl-methyl]-6-methyl-pyridin-3-ol (p-4, compound 154, 33%, melting point: 228° C.). Fraction 2 was taken up in diisopropylether. The precipitate was filtered off and dried, yielding 0.03 g of 2-[5,7-dimethyl-2-(3-morpholin-4-yl-propylamino)-benzoimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol (p-5, compound 156, 10%, melting point: 234° C.).

Example 17

The mixture of q-1 (0.06 mol) and POCl₃ (100 ml) was heated at 100° C. and HCl 12N (2.5 ml) was added drop wise very carefully. The reaction was then stirred during 12 hours at 120° C. and allowed to cool down to room temperature. The solvent was evaporated under reduced pressure and a 10% solution of potassium carbonate in water was added to the residue. The resulting precipitate was filtered off; rinsed with water and dried, yielding 10 g of q-2 (93%, melting point: 152° C.).

q-2 (0.022 mol) and q-3 (0.088 mol) were stirred at 130° C. during 12 hours. The reaction was then allowed to cool down to room temperature, the residue was taken up in acetone and the precipitate was filtered off. The acetone solution was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/MeOH/NH₄OH 95/5/0.1). The pure fractions were collected and the solvent was evaporated, yielding 5 g of q-4 (72%).

A mixture of q-4 (0.0158 mol), q-5 (0.019 mol) and potassium carbonate (0.0553 mol) in dimethylformamide (100 ml) was stirred at 70° C. for 24 hours. The solvent was evaporated until dryness. The residue was taken up in CH₂Cl₂/CH₃OH (90/10). The organic layer was washed with a 10% solution of K₂CO₃ in water, dried (over MgSO₄), filtered and the solvent was evaporated under reduced pressure. The residue was taken up in 2-propanone. The precipitate was filtered off, washed with H₂O and dried, yielding 5 g of q-6 and q-7 (50/50 mixture, 73%).

A mixture of q-6 and q-7 (0.0103 mol) in a 48% solution of HBr in water (50 ml) was stirred at 60° C. during 12 hours. The solvent was evaporated until dryness. The residue was taken up in CH₂Cl₂/CH₃OH (90/10). 10% solution of K₂CO₃ in water was added. The aqueous layer was saturated with K₂CO₃ (powder). The organic layer was separated, dried (over MgSO₄), filtered, and the solvent was evaporated until dryness, yielding 3.7 g of q-8 and q-9 (100%). This product was used directly in the next reaction step.

A mixture of q-8 (0.0006 mol), q-9 (0.0006 mol), N-(2-chloro-ethyl)-morpholine, HCl (0.0016 mol) and K₂CO₃ (0.0048 mol) in dimethylformamide (30 ml) was stirred at room temperature for 48 hours. The solvent was evaporated until dryness. The residue was taken up in CH₂Cl₂. The mixture was filtered. The filtrate was evaporated until dryness. The residue (1.2 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 90/10/0.5; 10 μm). Two fractions were collected and the solvent was evaporated, yielding 0.023 g of fraction 1 (4%) and 0.12 g of fraction 2 (18%). Fraction 1 was crystallized from CH₃OH/CH₃CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.02 g of 2-[5,7-dimethyl-2-(2-morpholin-4-ylethyl-piperidin-4-ylamino)-benzoindazol-1-ylmethyl]-6-methyl-pyridin-3-ol (q-10, compound 162, 3%, melting point: 226° C.). Fraction 2 was crystallized from CH₃OH/CH₃CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.1 g of 2-[4,6-dimethyl-2-(2-morpholin-4-ylethyl-piperidin-4-ylamino)-benzoimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol (q-11, compound 170, 15%, melting point: 237° C.).

Example 18

LiAlH₄ (0.0002 mol) was added at 5° C. to a mixture of 3-{4-[1-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-4,6-dimethyl-1H-benzoimidazol-2-ylamino]-piperidin-1-yl}-propionic acid ethyl ester (r-1; 0.00009 mol; melting point: 172° C.) in tetrahydrofuran (10 ml) under N₂ flow. The mixture was stirred at 5° C. for 1 hour, then at room temperature for 3 hours. A minimum of H₂O and ethylacetate were added. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue was crystallized from 2-propanone/CH₃CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.026 g of 2-{2-[1-(3-hydroxy-propyl)-piperidin-4-ylamino]-4,6-dimethyl-benzoimidazol-1-ylmethyl}-6-methyl-pyridin-3-ol (r-2; 68%, melting point: 209° C.).

A mixture of r-2 (0.0001 mol) and CH₂Cl₂ (15 ml) was cooled in a bath of ice. SOCl₂ (0.0005 mol) was added drop wise. The mixture was stirred at 5° C. for 1 hour, then at room temperature for 12 hours. SOCl₂ (0.0005 mol) was added. The mixture was stirred at room temperature for 4 hours. The solvent was evaporated until dryness, yielding 0.06 g of intermediate r-3 (HCl, 100%). This product was used directly in the next reaction step.

A mixture of r-3 (0.0001 mol), morpholine (0.0003 mol) and K₂CO₃ (0.0011 mol) in CH₃CN (15 ml) was stirred at 70° C. for 6 hours. The solvent was evaporated until dryness. The residue was taken up in CH₂Cl₂/H₂O. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (0.06 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 88/11/1; 5 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.016 g of 2-[4,6-dimethyl-2-(2-morpholin-4-ylpropyl-piperidin-4-ylamino)-benzoimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol (r-4, compound 161, 18%, melting point: 223° C.).

Example 19

A mixture of s-1 (0.166 mol) and urea (0.199 mol) in xylene (300 ml) was stirred under reflux for 12 hours. The reaction was cooled down to room temperature. The precipitate was filtered off, rinsed with xylene and diisopropylether, and then dried, yielding 32 g of intermediate s-2 (93%, melting point: >260° C.).

A mixture of s-2 (0.073 mol) in POCl₃ (150 ml) was stirred at 100° C. HCl conc. (around 1.5 ml) was added drop wise very carefully until the dissolution of s-2. The mixture was stirred at 120° C. for 6 hours. The solvent was evaporated until dryness. The residue was taken-up in H₂O/ice, basified with K₂CO₃ (powder) and extracted with ethylacetate+10% methanol. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness, yielding 13.5 g of intermediate s-3 (83%, melting point: 178° C.).

A mixture of s-3 (0.051 mol) and s-4 (0.056 mol) was stirred at 160° C. for 2 hours. The residue was taken-up in CH₂Cl₂/H₂O and basified with a 10% solution of K₂CO₃ in water. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/methanol/NH₄OH 95/5/0.5). The pure fractions were collected and the solvent was evaporated, yielding 15.3 g of intermediate s-5 (79%).

A mixture of s-5 (0.0396 mol), s-6 (0.059 mol) and K₂CO₃ (0.1584 mol) in CH₃CN (180 ml) was stirred and refluxed for 12 hours. The solvent was evaporated until dryness. The residue was taken up in CH₂Cl₂. The organic layer was washed with H₂O, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (20 g) was purified by column chromatography over silica gel (eluent: Toluene/2-propanol/NH₄OH 85/15/1; 20-45 μm). Two fractions were collected and the solvent was evaporated, yielding 5.3 g of fraction 1 (27%) and 6.3 g of fraction 2 (32%). Fraction 1 was crystallized twice in 2-propanone/CH₃CN/diisopropylether. The precipitate was filtered off and dried, yielding 4.9 g of intermediate s-7 (25%, melting point: 179° C.).

LiAlH₄ (0.009 mol) was added portion wise to a mixture of s-7 (0.003 mol) in tetrahydrofuran (60 ml) at 5° C. under N₂ flow. The reaction was stirred at 5° C. for 1 hour and then at room temperature for 12 hours. Ethylacetate and H₂O were added carefully and the aqueous layer was saturated with K₂CO₃ (powder). The organic layer was separated, dried (over MgSO₄) and then filtered over celite. The filtrate was evaporated until dryness, yielding 1.3 g of intermediate s-8 (97%). The crude product was used directly in the next reaction step.

A mixture of s-8 (0.0028 mol) and Pd/C 10% (2.5 g) in CH₃OH (40 ml) was hydrogenated at 40° C. for 12 hours under an 8 bar pressure, then filtered over celite. Celite was washed with a solution of CH₃OH/tetrahydrofuran (50/50). The filtrate was evaporated until dryness, yielding 1.8 g of intermediate s-9 (95%, melting point: 260° C.).

A mixture of s-9 (0.0027 mol), N-(2-chloro-ethyl)-morpholine, HCl (0.0032 mol) and triethylamine (0.0067 mol) in dimethylformamide (40 ml) was stirred at 50° C. for 48 hours, poured into ice water and extracted 3 times with CH₂Cl₂. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH; 85/14/1; 35-70 μm). The pure fractions were collected and the solvent was evaporated. The residue was taken up in 2-propanone/diisopropylether. The precipitate was filtered off and dried, yielding 0.8 g of intermediate s-10 (compound 168, 61%, melting point: 147° C.).

A mixture of s-10 (0.0014 mol) and MnO₂ (1.6 g) in CH₂Cl₂ (50 ml) was stirred at room temperature for 12 hours, and then filtered over celite. The solvent of the filtrate was evaporated until dryness. The residue was crystallized from 2-propanone/diisopropylether. The precipitate was filtered off and dried, yielding 0.47 g of intermediate s-11 (67%, melting point: 136° C.).

CH₃CO₂H (0.3 ml) was added at room temperature to a mixture of s-11 (0.0005 mol), 3,5-dimethyl-aniline (0.0006 mol) and NaBH₃CN (0.0006 mol) in CH₃CN (30 ml). The mixture was stirred at room temperature for 30 minutes. CH₃CO₂H (0.3 ml) was added. The mixture was stirred at room temperature for 6 hours. The solvent was evaporated until dryness. The residue was taken up in CH₂Cl₂. The organic layer was washed with a 10% solution of K₂CO₃ in water, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (0.26 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 90/10/1; 5 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.12 g, 36%) was crystallized from CH₃CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.07 g of 2-{6-[(3,5-dimethyl-phenylamino)-methyl]-2-[2-(2-morpholin-4-yl-ethyl)-piperidin-4-ylamino]-benzoimidazol-1-ylmethyl}-6-methyl-pyridin-3-ol (s-12, compound 163, 21%, melting point: 150° C.).

Example 20

Benzyl-diethylphosphonate (0.0019 mol) was added to a mixture of NaH (0.0037 mol) in tetrahydrofuran (15 ml) at 5° C. under N₂ flow. The mixture was stirred at 5° C. for 30 minutes. A solution of t-1 (0.0006 mol) in tetrahydrofuran (10 ml) was added drop wise. The mixture was stirred at 5° C. for 1 hour, then at room temperature for 12 hours. H₂O was added. The mixture was extracted with ethylacetate. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue was crystallized from CH₃OH. The precipitate was filtered off and dried, yielding 0.13 g of 6-methyl-2-{2-[2-(2-morpholin-4-yl-ethyl)-piperidin-4-ylamino]-6-styryl-benzoimidazol-1-ylmethyl}-pyridin-3-ol (t-2; compound 169, 37%, melting point: 224° C.).

A mixture of t-2 (0.0002 mol) and Pd/C 10% (0.035 g) in CH₃OH (5 ml) and tetrahydrofuran (5 ml) was hydrogenated at room temperature for 6 hours under a 8 bar pressure, and then filtered over celite. Celite was washed with H₂O. The filtrate was evaporated until dryness. The residue was taken up in 2-propanone. The precipitate was filtered, washed with H₂O and dried, yielding 0.08 g of 6-methyl-2-{2-[2-(2-morpholin-4-yl-ethyl)-piperidin-4-ylamino]-6-phenethyl-benzoimidazol-1-ylmethyl}-pyridin-3-ol (t-3, compound 165, 72%, melting point: 159° C.).

Example 21

A mixture of u-1 (mixture cis+trans) (0.0379 mol), u-2 (0.0416 mol) and K₂CO₃ (0.1136 mol) was stirred at 80° C. for 12 hours. H₂O was added. The mixture was extracted with CH₂Cl₂. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated. The residue (10 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1, 35-70 μm). Two fractions were collected and the solvent was evaporated, yielding 3 g of intermediate u-3 (trans) (29%) and 7.3 g of intermediate u-4 (cis) (71%).

A mixture of u-4 (0.0279 mol) in a 3N solution of HCl in water (50 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for 12 hours. K₂CO₃ (powder) was added. CH₂Cl₂ was added. The aqueous layer was saturated with K₂CO₃ powder). The mixture was extracted with CH₂Cl₂. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated, yielding 4.39 g of intermediate u-6 (93%). Analogously, u-5 was prepared.

A mixture of u-7 (0.0085 mol) and u-6 (0.0255 mol) was stirred at 120° C. for 4 hours. A 10% solution of K₂CO₃ in water was added. The aqueous layer was saturated with K₂CO₃ (powder). The mixture was extracted with CH₂Cl₂. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated. The residue (4.1 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 90/10/1; 15-40 μm). The pure fractions were collected and the solvent was evaporated, yielding 1.6 g of intermediate u-8 (59%).

A mixture of u-8 (0.0048 mol), u-9 (0.0058 mol) and K₂CO₃ (0.0145 mol) in dimethylformamide (30 ml) was stirred at room temperature for 24 hours, poured into H₂O, saturated with K₂CO₃ (powder) and extracted with CH₂Cl₂/CH₃OH. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (3.3 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 90/10/0.5; 15-40 μm). Two fractions were collected and the solvent was evaporated, yielding 0.55 g of intermediate u-10 (26%) and 0.36 g of intermediate u-11 (17%). A small fraction of intermediate u-10 was crystallized from 2-propanone/CH₃CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.04 g (compound 175, melting point: 199° C.). A small fraction of intermediate u-11 was crystallized from 2-propanone/CH₃CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.04 g (compound 187, melting point: 227° C.).

A mixture of u-10 (0.0011 mol) and MnO₂ (1 g) in CH₂Cl₂ (50 ml) and CH₃OH (3 ml) was stirred at room temperature for 12 hours, and then filtered over celite. Celite was washed with H₂O. The filtrate was evaporated until dryness, yielding 0.5 g of intermediate u-12 (100%). The crude product was used directly in the next reaction step.

CH₃CO₂H (0.25 ml) was added to a mixture of u-12 (0.0005 mol), 3,5-dimethyl-aniline (0.0006 mol) and NaBH₃CN (0.0006 mol) in CH₂Cl₂ (30 ml). The mixture was stirred at room temperature for 12 hours. A 10% solution of K₂CO₃ in water was added. The mixture was saturated with K₂CO₃ (powder). The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.1; 35-70 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.25 g, 80%) was crystallized from 2-propanone/CH₃CN/diisopropylether. The precipitate was filtered off and dried, yielding 0.183 g of 2-{2-[3-(2,6-dimethyl-morpholin-4-yl)-propylamino]-6-[(3,5-dimethyl-phenylamino)-methyl]-benzoimidazol-1-ylmethyl}-6-methyl-pyridin-3-ol (u-13, compound 172, 59%, melting point: 192° C.).

Example 22

A mixture of morpholine (0.0116 mol), epichlorohydrin (0.0116 mol) in ethanol (30 ml) was stirred at room temperature for 24 hours. The solvent was evaporated until dryness, yielding 2.08 g of intermediate v-1 (100%). The crude product was used directly in the next reaction step.

A mixture of v-1 (0.0116 mol), potassium phthalimide (0.01276 mol) in dimethylformamide (25 ml) was stirred under reflux for 4 hours. The solvent was evaporated. The residue was taken up in CH₂Cl₂ and washed with H₂O. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness, yielding 3.4 g of intermediate v-2 (100%). The crude product was used directly in the next reaction step.

A mixture of v-2 (0.116 mol) and hydrazine (15 ml) in ethanol (350 ml) was stirred at 80° C. for 1 hour. The reaction was cooled down to room temperature. The precipitate was filtered off and rinsed with ethanol and CH₂Cl₂. A 10% solution of K₂CO₃ in water was added. The aqueous layer was saturated with K₂CO₃ (powder) and extracted with CH₂Cl₂/CH₃OH (95/5). The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness, yielding 14.8 g of intermediate v-3 (80%). The crude product was used directly in the next reaction step.

Intermediate v-5 was prepared in an analogous way to the procedure described for intermediate u-8. Intermediates v-7 (2 g; 31%, melting point: 184° C.) and v-8 (2.1 g; 33%, melting point: 208° C.) were prepared in an analogous way to the procedure described for preparing u-10 and u-11. Intermediate v-9 (0.77 g; 77%, melting point: 152° C.) was prepared in an analogous way to the procedure described for intermediate u-12.

CH₃CO₂H (0.2 ml) was added at room temperature to a mixture of v-9 (0.00047 mol), 3,5-dimethyl-aniline (0.00056 mol) and BH₃CN— on solid support (0.000705 mol) in CH₃OH (10 ml). The mixture was sired at room temperature for 18 hours. The solid support was filtered off, rinsed with CH₃OH and the filtrate was concentrated. The residue was taken up with a 10% solution of K₂CO₃ in water. The aqueous layer was saturated with K₂CO₃ (powder) and extracted with CH₂Cl₂/CH₃OH (95/5). The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.1; 35-70 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.2 g) was crystallized from 2-propanone/diisopropylether. The precipitate was filtered off and dried, yielding 0.154 g of 2-[6-[(3,5-dimethyl-phenylamino)-methyl]-2-(2-hydroxy-3-morpholin-4-yl-propyl-amino)-benzoimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol (v-10; compound 171, 62%, melting point: 198° C.).

Example 23

Intermediate w-2 was prepared in an analogous way to the procedure described for intermediate u-8. Intermediates w-4 (0.28 g; 28%) and w-5 (0.025 g; 26%) were prepared in an analogous way to the procedure described for intermediate u-10 and u-11. Intermediate w-6 (0.020 g; 80%) was prepared in an analogous way to the procedure described for intermediate u-12.

2-[5-[(3,5-Dimethyl-phenylamino)-methyl]-2-(3-[1,4]oxazepan-4-yl-propylamino)-benzoimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol (w-7, compound 174, 0.007 g; 28%) was prepared in an analogous way to the procedure described for compound v-10.

Example 24

A mixture of x-1 (0.0635 mol), x-2 (0.0635 mol) and K₂CO₃ (0.19 mol) in CH₃CN (110 ml) was stirred at 80° C. for 12 hours, then cooled to room temperature, poured on ice and extracted with CH₂Cl₂. The organic layer was separated, dried (over MgSO₄), filtered, and the solvent was evaporated until dryness. Yield: 20.2 g (96%). HCl 3N (200 ml) and tetrahydrofuran (200 ml) were then added and the reaction was stirred at room temperature for 12 hours. K₂CO₃ was added. CH₂Cl₂ was added. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. Yield: 8.4 g of intermediate x-3 (60%).

A mixture of x-4 (0.0173 mol) and x-3 (0.026 mol) was stirred at 125° C. for 4 hours, and then taken up in CH₂Cl₂/CH₃OH. The organic layer was washed with saturated K₂CO₃ solution, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (9 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 90/10/0.5; 20-45 μm). Two fractions were collected and the solvent was evaporated. Yield: 0.7 g of intermediate x-5 (10%).

A mixture of x-5 (0.0018 mol), x-6 (0.0022 mol) and K₂CO₃ (0.0056 mol) in dimethylformamide (20 ml) was sired at room temperature for 12 hours, poured on ice, saturated with K₂CO₃ and extracted with CH₂Cl₂. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (1.4 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 93/7/0.5; 5-40 μm). Two fractions were collected and the solvent was evaporated. Yield: 0.29 g of intermediate x-7 (31%) and 0.2 g of intermediate x-8 (22%).

SOCl₂ (0.0015 mol) was added at 5° C. to a mixture of x-7 (0.0003 mol) in CH₂Cl₂ (20 ml). The mixture was stirred at 5° C. for 2 hours, and then stirred at room temperature for 12 hours. The solvent was evaporated until dryness. The residue was taken up in Diisopropylether. The precipitate was filtered off and dried. Yield: 0.198 g of intermediate x-9 (HCl salt, 100%).

A mixture of x-9 (0.0003 mol), 3,5-dimethylaniline (0.0003 mol) and K₂CO₃ (0.0015 mol) in dimethylformamide (20 ml) was stirred at 80° C. for 4 hours, poured into ice water, saturated with K₂CO₃ and extracted with CH₂Cl₂/CH₃OH. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (0.17 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 93/7/0.5; 10 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.023 g of intermediate x-10 (13%).

LiAlH₄ (0.00008 mol) was added at 5° C. to a mixture of x-10 (0.00004 mol) in tetrahydrofuran (10 ml). The mixture was stirred at 5° C. for 2 hours, poured into H₂O. CH₂Cl₂ was added. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated. The residue (0.023 g) was purified by column chromatography over silica gel (eluent CH₂Cl₂/CH₃OH/NH₄OH 92/8/0.5; 10 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.009 g of 2-(6-[(3,5-Dimethyl-phenylamino)-methyl]-2-{3-[2-(2-hydroxy-ethyl)-morpholin-4-yl]-propylamino}-benzoimidazol-1-ylmethyl)-6-methyl-pyridin-3-ol (x-11, compound 181, 41%).

Example 25

A mixture of y-2 (0.0012 mol) and y-1 (0.0073 mol) was stirred at 160° C. for 2 hours, and then taken up in CH₂Cl₂/CH₃OH. The organic layer was washed with K₂CO₃ 10%, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (1.5 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 96/4/0.2; 15-40 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.08 g of intermediate y-3 (11%).

A solution of y-3 (0.0001 mol) in NH₃/CH₃OH 7N (15 ml) was stirred at 80° C. in a sealed vessel for 24 hours. The solvent was evaporated until dryness. Yield: 0.075 g of intermediate y-4 (100%). The crude compound was used directly in the next reaction step.

A mixture of y-4 (0.0001 mol) and Pd/C (0.03 g) in CH₃OH (30 ml) was hydrogenated at room temperature for 2 hours under a 3 bar pressure, then filtered over celite. Celite was washed with H₂O. The filtrate was evaporated until dryness. The residue was crystallized from 2-propanone/Diisopropylether. The precipitate was filtered off and dried. Yield: 0.034 g of 2-(4-{3-[1-(3-Hydroxy-6-methyl-pyridin-2-ylmethyl)-4,6-dimethyl-1H-benzoimidazol-2-ylamino]-propyl}-morpholin-2-yl)-acetamide (y-5, compound 191, 55%, melting point: 148° C.).

Example 26

SOCl₂ (0.0035 mol) was added drop wise at 5° C. to a mixture of z-1 (0.0007 mol) in CH₂Cl₂ (30 ml). The mixture was stirred at 5° C. for 2 hours, and then stirred at room temperature for 12 hours. The solvent was evaporated until dryness. The residue was taken up in Diisopropylether. The precipitate was filtered, washed with H₂O and dried. Yield: 0.415 g of intermediate z-2 (4 HCl, 100%).

A mixture of z-2 (0.0014 mol), z-3 (0.0016 mol) and K₂CO₃ (0.007 mol) in dimethylformamide (80 ml) was sired at 80° C. for 4 hours, poured into ice water, saturated with K₂CO₃ and extracted with CH₂Cl₂. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (1 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 93/7/1; 10 μm). The pure fractions were collected and the solvent was evaporated. Yield: 0.22 g of the free base (26%). This fraction was dissolved in 2-propanone/diisopropylether/HCl 7N and converted into the hydrochloric acid salt. The precipitate was filtered off and dried. Yield: 0.25 g of 4-{(3,5-Dimethyl-phenyl)-[3-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-2-(2-hydroxy-3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-butyramide, HCl salt (z-4, compound 178, 4 HCl, 24%, melting point: 164° C.).

Example 27

A mixture of aa-1 (0.0104 mol), aa-2 (0.0114 mol) and Cs₂CO₃ (0.0034 mol) in dimethylformamide (40 ml) was stirred at room temperature for 12 hours, poured on ice, saturated with K₂CO₃ and extracted with CH₂Cl₂. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (8.6 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 94/6/0.5). Two fractions were collected and the solvent was evaporated. Yield F1 and F2. F1 was crystallized from CH₃OH/2-propanone/diisopropylether. The precipitate was filtered and dried. Yield: 0.75 g of intermediate aa-3 (compound 311, 16%, melting point: 160° C.). F2 was crystallized from few CH₃OH/2-propanone/diisopropylether. The precipitate was filtered, washed with diisopropylether and dried. Yield: 0.4 g of intermediate aa-4 (compound 336, 9%, melting point: 202° C.).

A mixture of aa-3 (0.0005 mol) and MnO₂ (2.5 g) in CH₂Cl₂ (50 ml) and CH₃OH (few quantity) was stirred at room temperature for 3 hours, and then filtered over celite. Celite was washed with CH₂Cl₂. The filtrate was evaporated until dryness. Yield: 0.21 g of intermediate aa-5 (84%).

A mixture of aa-5 (0.0004 mol), aa-6 (0.0005 mol) and BH₃CN— on solid support (0.0007 mol) in CH₃OH (15 ml) and CH₃CO₂H (1.5 ml) was stirred at room temperature for 24 hours, and then filtered. The filtrate was evaporated until dryness. The residue (0.25 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.5; 5 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off and dried. Yield: 0.068 g of 2-(2-{[3-(2,3-Dimethyl-5,6,7,8-tetrahydroquinoxalin-5-yl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-4-methyl-phenyl)-ethanol (aa-7, compound 193, 25%, melting point: 162° C.).

Example 28

SOCl₂ (0.0016 mol) was added drop wise at 5° C. to a solution of aa-3 (0.0003 mol) in CH₂Cl₂ (0.0016 mol). The mixture was stirred at 5° C. for 2 hours, and then stirred at room temperature for 12 hours. The solvent was evaporated until dryness. The residue was taken up in diisopropylether. The precipitate was filtered off and dried. Yield: 0.16 g of intermediate ab-1 (4 HCl, 78%).

A mixture of ab-1 (0.0003 mol), ab-2 (0.0003 mol) and Cs₂CO₃ (0.0016 mol) in dimethylformamide (25 ml) was stirred at 80° C. for 3 hours, poured on ice, saturated with K₂CO₃ and extracted with CH₂Cl₂. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (0.45 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 89/10/1; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.07 g) was crystallized from 2-propanone/diisopropylether. The precipitate was filtered, washed with H₂O and dried. Yield: 0.07 g of 4-{(3,5-Dimethyl-phenyl)-[3-(2,3-dimethyl-5,6,7,8-tetrahydro-quinoxalin-5-yl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-butyramide (ab-3, compound 213, 17%, melting point: 109° C.).

Example 29

Intermediates ac-3 (compound 327, 24%, melting point: 254° C.) and ac-4 (compound 359, 17%, melting point: 242° C.) were synthesized according to the procedure described for intermediates aa-3 and aa-4 but using K₂CO₃ instead of Cs₂CO₃.

Intermediate ac-5 (80%, melting point: 208° C.) was synthesized according to the procedure described for intermediate aa-5.

Final compound 2-[6-{[2-(2-Hydroxy-ethyl)-5-methyl-phenylamino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzoimidazol-1-ylmethyl]-pyridin-3-ol (ac-7, compound 192, 81%, melting point: 192° C.) was synthesized according to the procedure described for final compound aa-7.

Example 30

Intermediate ad-1 (4 HCl, 100%) was synthesized according to the procedure described for intermediate ab-1.

Final compound 4-{(3,5-Dimethyl-phenyl)-[3-(3-hydroxy-pyridin-2-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-butyramide (ad-3, compound 228, 17%, melting point: 170° C.) was synthesized according to the procedure described for final compound ab-3.

Example 31

A solution of ae-2 (0.0246 mol) in dimethylformamide (30 ml) was added to a mixture of ae-1 (0.0205 mol) and NaH (0.0226 mol) in dimethylformamide (70 ml). The mixture was stirred at 50° C. for 48 hours. The solvent was evaporated until dryness. H₂O was added. The mixture was extracted three times with CH₂Cl₂. The organic layer was separated, dried (over MgSO₄), filtered and the solvent was evaporated until dryness. The residue (11 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 95/5/0.5 to 93/710.5; 15-40 μm). Two fractions were collected and the solvent was evaporated. Yield: 3.6 g of intermediate ae-3 (41%) and 2.3 g of intermediate ae-4 (26%).

Intermediate ae-5 (62%, melting point: 130° C.) was synthesized according to the procedure described for intermediate aa-5.

Final compound 3-(4-Methyl-2-{[2-(3-morpholin-4-yl-propylamino)-3-(3,5,6-trimethyl-pyrazin-2-ylmethyl)-3H-benzoimidazol-5-ylmethyl]-amino}-phenyl)-propan-1-ol (ae-7, compound 255, 41%, melting point: 120° C.) was synthesized according to the procedure described for final compound aa-7.

Example 32

Intermediate af-1 (4 HCl, 100%) was synthesized according to the procedure described for intermediate ab-1.

Final compound 2-{(3,5-Dimethyl-phenyl)-[2-(3-morpholin-4-yl-propylamino)-3-(3,5,6-trimethyl-pyrazin-2-ylmethyl)-3H-benzoimidazol-5-ylmethyl]-amino}-ethanol (af-3, compound 233, 24%, melting point: 140° C.) was synthesized according to the procedure described for final compound ab-3 but using K₂CO₃ instead of Cs₂CO₃.

Example 33

Intermediates ag-3 (31%) and ag-4 (30%) were synthesized according to the procedure described for intermediates aa-3 and aa-4.

Intermediate ag-5 (86%) was synthesized according to the procedure described for intermediate aa-5.

Final compound 3-(2-{[3-(6-Bromo-pyridin-2-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-4-methyl-phenyl)-propan-1-ol (ag-7, compound 267, 56%, melting point: 141° C.) was synthesized according to the procedure described for final compound aa-7.

Example 34

Intermediate ah-1 (4 HCl, 89%) was synthesized according to the procedure described for intermediate ab-1.

Final compound 4-[[3-(6-Bromo-pyridin-2-ylmethyl)-2-(3-morpholin-4-yl-propyl-amino)-3H-benzoimidazol-5-ylmethyl]-(3,5-dimethyl-phenyl)-amino]-butyramide (ah-3, compound 261, 18%, melting point: 82° C.) was synthesized according to the procedure described for final compound ab-3.

Example 35

Intermediates ai-3 (compound 325, 19%, melting point: 167° C.) and ai-4 (compound 358, 9%, melting point: 173° C.) were synthesized according to the procedure described for intermediates ae-3 and ae-4.

Intermediate ai-5 (100%) was synthesized according to the procedure described for intermediate aa-5.

Final compound 3-(4-Methyl-2-{[3-(1-methyl-1H-benzoimidazol-4-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-phenyl)-propan-1-ol (ai-7, compound 218, 70%, melting point: 198° C.) was synthesized according to the procedure described for final compound aa-7.

Example 36

Intermediate aj-1 (4 HCl, 100%) was synthesized according to the procedure described for intermediate ab-4.

Final compound 4-{(3,5-Dimethyl-phenyl)-[3-(1-methyl-1H-benzoimidazol-4-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-butyramide (aj-3, compound 230, 21%, melting point: 206° C.) was synthesized according to the procedure described for final compound ab-3.

Example 37

Intermediates ak-3 (compound 346, 16%, melting point: 135° C.) and ak-4 (compound 360, 12%, melting point: 138° C.) were synthesized according to the procedure described for intermediates aa-3 and aa-4 but using K₂CO₃ instead of Cs₂CO₃.

Intermediate ak-5 (70%) was synthesized according to the procedure described for intermediate aa-5.

Final compound 3-(2-{[3-(3-Methoxy-6-methyl-pyridin-2-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-4-methyl-phenyl)-propan-1-ol (ak-7, compound 219, 38%, melting point: 132° C.) was synthesized according to the procedure described for final compound aa-7.

Example 38

Intermediate al-1 (4 HCl, 100%) was synthesized according to the procedure described for intermediate ab-1.

Final compound-{(3,5-Dimethyl-phenyl)-[3-(3-methoxy-6-methyl-pyridin-2-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-butyramide (al-3, compound 210, 16%, melting point: 130° C.) was synthesized according to the procedure described for final compound ab-3.

Example 39

Intermediates am-3 (compound 308, 8%, melting point: 230° C.) and am-4 (compound 322, 12%, melting point: 235° C.) were synthesized according to the procedure described for intermediates aa-3 and aa-4.

Intermediate am-5 (46%) was synthesized according to the procedure described for intermediate aa-5.

Final compound 4-Bromo-2-[6-{[2-(3-hydroxy-propyl)-5-methyl-phenylamino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzoimidazol-1-ylmethyl]-phenol (am-7, compound 201, 42%, melting point: 134° C.) was synthesized according to the procedure described for final compound aa-7.

Example 40

Intermediates an-3 (22%, melting point: 198° C.) and an-4 (19%, melting point: 200° C.) were synthesized according to the procedure described for intermediates aa-3 and aa-4 but using K₂CO₃ instead of Cs₂CO₃.

Intermediate an-5 (82%, melting point 148° C.) was synthesized according to the procedure described for intermediate aa-5.

Final compound 3-(4-Methyl-2-{[2-(3-morpholin-4-yl-propylamino)-3-quinolin-8-ylmethyl-3H-benzoimidazol-5-ylmethyl]-amino}-phenyl)-propan-1-ol (an-7, compound 234, 50%, melting point: 165° C.) was synthesized according to the procedure described for final compound aa-7.

Example 41

Intermediate ao-1 (4 HCl, 100%) was synthesized according to the procedure described for intermediate ab-1.

Final compound 4-{(3,5-Dimethyl-phenyl)-[2-(3-morpholin-4-yl-propylamino)-3-quinolin-8-ylmethyl-3H-benzoimidazol-5-ylmethyl]-amino}-butyramide (ao-3, compound 223, 16%, melting point: 154° C.) was synthesized according to the procedure described for final compound ab-3 but using K₂CO₃ instead of Cs₂CO₃.

The following tables list compounds that were prepared according to any one of the above examples.

TABLE 1

Comp. Mass Melting Synthesis No. R²a R³a Activity (MH+) point/salt scheme  1 H

10   556 205° C. K  2 H

10   623 210° C. K  3 H

9.9 559 208° C. K  4 H

9.9 579 205° C. K  5 H

9.8 561 K  6 H

>9.6   557 202° C. K  7 H

9.6 545 199° C. K  8 H

9.6 555 178° C. K  9 H

9.6 561 K 10 H

9.6 555 K 11 H

9.6 609 K 12 H

9.6 609 170° C. K 13 H

9.5 613 232° C. K 14 H

9.4 575 185° C. K 15 H

9.3 573 161° C. K 16 H

9.3 572 190° C. K 17 H

9.3 573 K 18 H

9.6 549 K 19 H

9.3 557 185° C. K 20 H

9.2 573 189° C. K 21 H

9.1 539 206° C. J 22 H

9.1 531 140° C. K 23 H

9   515 199° C. J 24 H

626 185° C. K 25 H

8.9 545 208° C. K 26 H

8.7 565 205° C. K 27 H

8.7 512 217° C. K 28 H

8.6 501 195° C. K 29 H

8.6 517 130° C. K 30 H

8.6 511 186° C. J 31 H

8.6 522 212° C. J 32 H

8.6 531 131° C. K 33 H

8.6 558 164° C. K 34 H

8.6 555 225° C. L 35 H

8.5 505 210° C. J 36 H

8.5 571 163° C. K 37 H

8.5 566 >260° C.   K 38 H

8.5 530 175° C. K 39 H

8.5 560 K 40 H

8.4 515 209° C. K 41 H

8.3 515 210° C. K 42 H

8.3 600 132° C. K 43 H

8.2 531 231° C. K 44 H

8.1 574 K 45 H

7.9 530 145° C. K 46 H

7.9 552 150° C. K 47 H

7.9 531 158° C. K 48 H

7.7 609 K 49 H

7.4 568 114° C. M 50 H

7.3 627 225° C. K 51

H 7.2 515 176° C. J 52 H —CH₂—OH 7.2 412 192° C. A 53 —CH₂—OH H 5.6 412 134° C. A 54 H

613 194° C. K 55 H

597 228° C. K 56 H

613 220° C. K 57 H

597 230° C. K

TABLE 2 compounds prepared according to synthesis scheme N or O

Melting Comp. Mass point/ No. R^(4a) Activity (MH+) salt 58 —(CH₂)₂—OH 9.4 559 180° C. 59

9.6 600 170° C. 60

9.5 586 138° C. 61 —(CH₂)₄—OH 9.5 587 170° C. 62

9.4 601 121° C. 63 —(CH₂)₃—OH 9.3 573 137° C. 64 —(CH₂)₅—OH 9.3 601 120° C. 65

9   628 169° C. 66 —(CH₂)₂—NH₂ 8.9 558 196° C. 67

8.8 695 152° C. 68

8.7 642 169° C. 69 —(CH₂)₂—COOH 8.7 587 128° C. 70

8.6 679 175° C. 71

8.6 629 130° C. 72

8.5 615 136° C. 73

9.6 636 136° C. 74

9.5 650 105° C. 75

9.5 614 190° C. 76

9.4 650 120° C. 77

9.4 614 150° C. 78

9.2 601 205° C. 79

9.1 603 152° C. 80

9.1 665 120° C. 81

8.9 595 135° C. 82 —(CH₂)₂—OCH₃ 8.6 573 215° C. 83

8.6 649 168° C./HCl 84

8.5 615 230° C.

TABLE 3 compounds prepared according to synthesis scheme N or O

Comp Mass Melting No. R^(4a) R^(a) Activity (MH+) point/salt 85 —(CH₂)₂—OH 3-Br 9.3 609 210° C. 86 —(CH₂)₂—OH 5-CH₃ 9.3 545 205° C. 87

3-CH₃ 9.2 586 139° C. 88 —(CH₂)₂—OH 4-CN 9.1 556 195° C. 89

3-CH₃ 9   572 128° C. 90

5-Br 9   650 180° C. 91

5-CH₃ 8.9 636 140° C. 92 —(CH₂)₄—OH 3-CH₃ 8.8 573 169° C. 93 —(CH₂)₃—OH 3-CH₃ 8.7 559 109° C. 94

3-CH₃ 8.6 614 153° C. 95 —(CH₂)₃—OH 5-Br 8.6 623 120° C. 96

4-CN 8.6 597 170° C. 97 —(CH₂)₂—OH H 8.5 531 190° C. 98

5-CH₃ 8.5 636 125° C. 99 —(CH₂)₂—OH 3-[—C≡CH] 8.5 555 186° C. 100  —(CH₂)₂—N(CH₃)₂ 3-CH₃ 8.4 572 172° C. 101 

2-[—(CH₂)₂—OH] 8.3 588 175° C. 102

3-CH₃ 8.3 601 150° C. 103

6-[—(CH₂)₂—OH] 8.2 644 146° C. 104

3-[—(CH₂)₂—OH] 8.2 602 124° C. 105 —(CH₂)₂—OH

8.2 574 130° C. 106 phenyl 4-OH 8.1 579 175° C. 107 —(CH₂)₂—OH 6-[—(CH₂)₂—OH] 8.1 575 165° C. 108 H 6-[—CH₂—NH₂] 8   516 116° C. 109 phenyl 3-OH 7.9 579 135° C. 110 —(CH₂)₂—OH 6-CH₃ 7.8 545 165° C. 111 —(CH₂)₂—OH

7.6 574 145° C. 112

5-[—C≡CH] 9.5 632 142° C. 113

5-Br 9.3 636 140° C. 114

5-[—C≡CH] 9.3 596 162° C. 115

5-[—C≡CH] 9.3 582 147° C. 116

5-[—C≡CH] 8.7 597 134° C. 117

5-Br 8.6 637 160° C. 118

4-CN 8.6 583 195° C. 119

4-CN 8.6 570 115° C. 120

8.5 610 135° C. 121

5-F 8.3 549 195° C. 122 CH₃ 6-[—(CH₂)₂—OH] 7.5 555 175° C.

TABLE 4 compounds prepared according to synthesis scheme N or O

Comp. Mass Melting No. R^(4a) R^(a) R^(b) R^(c) Activity (MH+) point/salt 123

3-Cl H 5-Cl 9.6 640 185° C. 124

3-Cl H 5-Cl 9.3 627 202° C. 125

3-CH₃ H 6-CH₃ 7.9 586 165° C. 126

2-CH₃ H 5-CH(CH₃)₂ 7.8 628   170° C./HCl 127

2-CH₃ 3-CH₃ 5-CH₃ 7.6 614 116° C. 128

3-CH₃ H 6-CH₃ 7.6 559 172° C. 129

2-CH₃ H 5-CH(CH₃)₂ 6.9 587 143° C. 130

2-CH₃ 3-CH₃ 5-CH₃ 6.9 573 199° C.

TABLE 5 compounds prepared according to synthesis scheme N or O

Comp. Mass Melting No. R4a R4b Activity (MH+) point/salt 131

9.3 623 168° C. 132

8.2 582 175° C. 133

8.1 574 215° C. 134

7.9 533 150° C. 135

7.8 590 129° C. 136

7.5 549 105° C. 137

7.3 573 185° C. 138

7.3 536 230° C.

TABLE 6 compounds prepared according to synthesis scheme N

Comp. Mass Melting No. R^(6a) R^(a) R^(b) Activity (MH+) point/salt 139

2-CH₃ 6-CH₃ 7.6 629 164° C. 140

3-CH₃ H 8.1 545 190° C. 141

3-OCH₃ H 8.1 561 170° C. 142

6-CH₃ H 8.1 573 143

2-CH₃ 6-CH₃ 8   559 162° C. 144

2-CH₃ 6-CH₃ 7.9 628 158° C. 145

2-CH₃ 6-CH₃ 7.9 586 140° C. 146

H 7.9 603 150° C. 147

2-CH₃ 6-CH₃ 7.8 587   156° C./HCl 148

2-CH₃ 6-CH₃ 8.4 636   171° C./HCl 149

2-CH₃ 6-CH₃ 7.9 187° C.   187° C./HCl 150

3-CH₃ 6-CH₃ 7.9 586 175° C. 151

3-CH₃ 6-CH₃ 7.7 559 210° C.

Compound prepared according to scheme N:

Mass Comp. No. Activity (MH+) Melting point/salt 152 8.1 549 168° C.

Compound prepared according to scheme N:

Mass Comp. No. Activity (MH+) Melting point/salt 153 7.3 527 212° C.

TABLE 7 compounds prepared according to synthesis scheme P

Melting Comp. Activ- Mass point/ No. R^(3b) R^(2a) R^(3a) R^(2b) ity (MH+) salt 154 —CH₃ H —CH₃ H 6.9 410 228° C. 155 H H H H 6.8 382 203° C. 156 H —CH₃ H —CH₃ 4.9 410 234° C.

TABLE 8

Comp. Mass Melting No. R^(2a) R^(3a) Activity (MH+) point/salt 157 H

6.3 576 186° C. 158

H <4 515 170° C. 159 H

4.7 515 168° C. 160 H

<5 529 172° C.

TABLE 9

Comp. Mass Melting Synthesis No. n R^(3b) R^(2a) R^(3a) R^(2b) Activity (MH+) point/salt scheme 161 3 —CH₃ H —CH₃ H 8.6 493 223° C. R 162 2 —CH₃ H —CH₃ H 7.9 479 226° C. Q 163 2 H H

H 7.9 584 150° C. S 164 2 H H

H 7.5 570 130° C. S 165 2 H H

H 6.9 555 159° C. T 166 2 —CH₃ H H H 6.8 465 238° C. Q 167 2 H

H H 6.7 553 225° C. T 168 2 H H —CH₂—OH H 6.5 481 147° C. S 169 2 H H

H 6.2 553 224° C. T 170 2 H —CH₃ H —CH₃ 6.1 479 237° C. Q

TABLE 10

Comp. Mass Melting Synthesis No. Q R^(3a) Activity (MH+) point/salt scheme 171

8.6 531 198° C. V 172

7.8 543 192° C. U 173

7.7 543 169° C. U 174

8.6 529 — W 175

—CH₂—OH 6.2 440 199° C. U 176

H 5.7 410 205° C. P 177

—CH₂—OH 5.7 440 202° C. U 178

9.6 750 164° C./HCl Z 179

9.6 561 210° C. N 180

9.3 625 156° C./HCl Z 181

8.2 559 — X 182

—CH₂—OH 7.1 428 212° C. A

TABLE 11

Comp. Mass Melting Synthesis No. Q R^(2a) Activity (MH+) point/salt scheme 183

6.7 529 198° C. W 184

6.3 543 209° C. U 185

7.7 543 169° C. U 186

—CH₂—OH 4.9 440 212 U 187

—CH₂—OH <4 440 227° C. U 188

—CH₂—OH <4 456 210° C. X 189

—CH₂—OH <4 428 165° C. A

TABLE 12

Comp. Mass Melting Synthesis No. Q Activity (MH+) point/salt scheme 190

6.9 454 168° C. Y 191

6.8 467 148° C. Y

TABLE 13

Comp. Mass Melting Synthesis No. G¹—R¹ R^(2a) R^(3a) Activity (MH+) point/salt scheme 192

H

9.3 531 192° C. AC 193

H

9.3 584 162° C. AA 194

H

9.3 584 — AA 195

H

9.3 584 — AA 196

H

9.3 570 — AA 197

H

9.3 554 198° C. AA 198

H

9.3 570 — AA 199

H

9.3 569 — AA 200

H

9.3 597 153° C. AA 201

H

9.3 622 134° C. AM 202

H

9.3 542 208° C. AC 203

H

9.3 619 212° C. AM 204

H

9.2 556 — AA 205

H

9.2 569 — AA 206

H

9.2 541 211° C. AC 207

H

9.1 598 130° C. AA 208

H

9.1 554 — AA 209

H

9.1 605 165° C. AA 210

H

9 614 130° C. AL 211

H

9 570 205° C. AA 212

H

9 570 — AA 213

H

8.8 639 109° C. AB 214

H

8.8 540 — AA 215

H

8.7 639 — AA 216

H

8.7 599 216° C. AC 217

H

8.7 676 149° C. AM 218

H

8.6 582 198° C. AI 219

H

8.6 573 132° C. AK 220

H

8.6 559 — AK 221

H

8.6 604 — AA 222

H

8.6 652 147° C. AA 223

H

8.5 620 154° C. AO 224

H

8.5 568 — AI 225

H

8.5 594 — AA 226

H

8.5 550 — AA 227

H

8.5 544 203° C. AM 228

H

8.4 568 170° C. AC 229

H

8.4 568 193° C. AI 230

H

8.4 623 206° C. AJ 231

H

8.4 594 220° C. AA 232

H

8.4 646 138° C. AI 233

H

8.3 572 140° C. AF 234

H

8.3 579 165° C. AW 235

H

8.3 575 182° C. AW 236

H

8.1 578 187° C. AI 237

H

7.9 554 — AI 238

H

7.9 581 — AI 239

H

7.9 559 — AK 240

H

7.9 573  85° C. AL 241

H

7.9 636 149° C. AI 242

H

7.8 623 — AI 243

H

7.8 558 — AE 244

H

7.8 528 — AE 245

H

7.8 579 202° C. AI 246

H

7.7 554 — AI 247

H

7.7 554 — AI 248

H

7.7 559 — AK 249

H

7.7 584  77° C. AG 250

H

7.7 633 200° C. AW 251

H 7.7 597 — AA 252

H

7.6 554 — AI 253

H

7.6 545 — AK 254

H 7.6 622 225° C. AM 255

H

7.6 572 120° C. AE 256

H

7.6 579 — AE 257

H

7.6 571 — AE 258

H

7.5 540 — AI 259

H

7.5 589 — AI 260

H

7.5 538 — AI 261

H

7.5 648  82° C. AH 262

H

7.5 529 — AK 263

H

7.5 544 — AE 264

H

7.5 543 — AE 265

H

7.4 572 — AK 266

H

7.4 528 — AE 267

H

7.3 607 141° C. AG 268

H

7.3 614 — AK 269

H

7.3 578 — AE 270

H

7.2 538 — AI 271

H

7.2 529 — AK 272

H

7.2 580 — AK 273

H

7.2 530 — AE 274

H

7.2 543 143° C. AG 275

H

7.2 529 — AG 276

H 7.2 554 — AA 277

H

7.1 568 — AI 278

H

7.1 607 161° C/HCl AG 279

H

7.1 531 — AK 280

H

7.1 545 — AK 281

H

7.1 543 156° C. AG 282

H

7.1 558 — AE 283

H

7.1 514 — AE 284

H

7.1 544 — AE 285

H

7.1 544 — AE 286

H 7.1 570 — AA 287

H 7.1 556 — AA 288

H

7 553 — AI 289

H

7 568 — AE 290

H

7 524 — AE 291

H

7 543 — AE 292

H 7 584 — AA 293

H 7 570 — AA 294

CH₂OH H 6.9 460  70° C. AG 295

H

6.9 524 — AI 296

H

6.9 553 — AI 297

H

6.9 579 — AK 298

H

6.9 545 — AK 299

H

6.9 613 — AE 300

H

6.9 544 — AE 301

H 6.8 545 218° C. AC 302

H

6.8 544 — AK 303

H

6.8 544 — AK 304

H 6.8 598 155° C. AA 305

H

6.7 534 — AI 306

H

6.7 525 — AK 307

H

6.7 545 — AK 308

H CH₂OH 6.7 475 230° C. AM 309

H 6.7 584 — AA 310

H 6.7 554 — AA 311

H CH₂OH 6.6 451 160° C. AA 312

H

6.6 578 — AI 313

H

6.6 588 — AI 314

H

6.6 515 — AK 315

H

6.5 587  75° C. AH 316

H 6.5 540 — AA 317

H 6.5 570 — AA 318

H 6.5 639 — AA 319

H

6.4 546 114° C. AG 320

H CH₂OH 6.3 484 102° C. AK 321

H 6.3 570 — AA 322

CH₂OH H 6.1 475 235° C. AM 323

H

6 499 — AG 324

H 6 569 — AA 325

H CH₂OH 5.9 435 167° C. AI 326

H 5.9 603 — AA 327

H CH₂OH 5.8 398 254° C. AC 328

H 5.8 582  90° C. AI 329

H 5.8 550 — AA 330

H

5.7 546 165° C. AH 331

H 5.7 594 — AA 332

CH₂OH H 5.5 484 138° C. AK 333

H

5.5 515 — AG 334

H

5.5 499 — AG 335

H

5.5 529 — AG 336

CH₂OH H 5.4 451 202° C. AA 337

H

5.4 532 — AG 338

H

5.4 485 — AG 339

H

5.3 545 — AG 340

H 5.3 569 — AA 341

H

5.2 542 — AG 342

H

5.1 496 — AG 343

H

5.1 550 — AG 344

H

5 539 — AG 345

H

5 584 — AG 346

H CH₂OH 4.9 426 135° C. AK 347

H

4.9 515 — AG 348

H 4.8 573 128° C. AK 349

H

4.8 518 — AG 350

H 4.7 543 146° C. AG 351

H CH₂OH 4.7 397 126° C. AM 352

H

4.5 514 — AG 353

H

4.5 515 — AG 354

H

4.4 553 — AG 355

H

4.4 517 — AG 356

CH₂OH H 4.4 397 122° C. AM 357

H

4.3 514 — AG 358

CH₂OH H 4.1 435 173° C. AI 359

CH₂OH H <4 398 242° C. AC 360

CH₂OH H <4 426 138° C. AK 361

H CH₂OH <4 399 — AG 362

CH₂OH H <4 399 — AG 363

H CH₂OH <4 396 — AG 364

CH₂OH H <4 396 124° C. AG 365

H <4 546  60° C. AG 366

H <4 607  73° C. AG 367

H

<4 532 — AG 368

H

<4 518 — AG 369

H

<4 542 — AG 370

H

<4 502 — AG 371

H

<4 552 — AG 372

H

<4 488 — AG 373

H

<4 504 — AG 374

H

<4 498 — AG 375

H

<4 518 — AG 376

H

<4 502 — AG 377

H

<4 587 — AG 378

H

<4 518 — AG 379

H

<4 517 — AG 380

H <4 572 145° C. AE 381

CH₂OH H <4 425 100° C. AE 382

H

<4 549 — AG 383

H

<4 501 — AG 384

H

<4 515 — AG

Example 42

In vitro Screening for Activity against Respiratory Syncytial Virus.

The percent protection against cytopathology caused by viruses (antiviral activity or EC₅₀) achieved by tested compounds and their cytotoxicity (CC₅₀) are both calculated from dose-response curves. The selectivity of the antiviral effect is represented by the selectivity index (SI), calculated by dividing the CC₅₀ (cytotoxic dose for 50% of the cells) by the EC₅₀ (antiviral activity for 50% of the cells). The tables in the above experimental part list the category to which each of the prepared compounds belongs: Compounds belonging to activity category “A” have an pEC₅₀ (−log of EC₅₀ when expressed in molar units) equal to or more than 7. Compounds belonging to activity category “B” have a pEC50 value between 6 and 7. Compounds belonging to activity category “C” have a pEC50 value equal to or below 6.

Automated tetrazolium-based colorimetric assays were used for determination of EC₅₀ and CC₅₀ of test compounds. Flat-bottom, 96-well plastic microtiter trays were filled with 180 μl of Eagle's Basal Medium, supplemented with 5% FCS (0% for FLU) and 20 mM Hepes buffer. Subsequently, stock solutions (7.8× final test concentration) of compounds were added in 45 μl volumes to a series of triplicate wells so as to allow simultaneous evaluation of their effects on virus- and mock-infected cells. Five five-fold dilutions were made directly in the microtiter trays using a robot system. Untreated virus controls, and HeLa cell controls were included in each test. Approximately 100 TCID₅₀ of Respiratory Syncytial Virus was added to two of the three rows in a volume of 50 μl. The same volume of medium was added to the third row to measure the cytotoxicity of the compounds at the same concentrations as those used to measure the antiviral activity. After two hours of incubation, a suspension (4×10⁵ cells/ml) of HeLa cells was added to all wells in a volume of 50 μl. The cultures were incubated at 37° C. in a 5% CO₂ atmosphere. Seven days after infection the cytotoxicity and the antiviral activity was examined spectrophotometrically. To each well of the microtiter tray, 25 μl of a solution of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was added. The trays were further incubated at 37° C. for 2 hours, after which the medium was removed from each cup. Solubilization of the formazan crystals was achieved by adding 100 μl 2-propanol. Complete dissolution of the formazan crystals were obtained after the trays have been placed on a plate shaker for 10 min. Finally, the absorbances were read in an eight-channel computer-controlled photometer (Multiskan MCC, Flow Laboratories) at two wavelengths (540 and 690 nm). The absorbance measured at 690 nm was automatically subtracted from the absorbance at 540 nm, so as to eliminate the effects of non-specific absorption. 

1. A compound which is 2-[6-{[2-(3-hydroxy-propyl)-5-methyl-phenylamino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol, or an, N-oxide, pharmaceutically acceptable salt, quaternary amine, or metal complex thereof.
 2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a compound as described in claim
 1. 3. A method for treating a respiratory syncytial viral infection comprising administering to a human subject in need thereof an anti-virally effective amount of the compound of claim
 1. 4. A method for treating a respiratory syncytial viral infection comprising administering to a human subject in need thereof an anti-virally effective amount of the composition of claim
 3. 5. A pharmaceutical composition made by mixing the compound of claim 1 and a pharmaceutically acceptable carrier.
 6. A process for making a pharmaceutical composition comprising mixing the compound of claim 1 and a pharmaceutically acceptable carrier.
 7. The pharmaceutical composition of claim 2, further comprising an additional antiviral agent.
 8. The pharmaceutical composition of claim 2, further comprising an antiviral agent selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.
 9. A method of treating a warm-blooded animal infected by a respiratory syncytial virus, or being at risk of infection by a respiratory syncytial virus, comprising administering to the warm-blooded animal an anti-virally effective amount of the compound of claim
 1. 10. A method for treating a respiratory synctial viral infection comprising administering to a human subject in need thereof an anti-virally effective amount of the compound of claim 1 and an additional antiviral agent.
 11. The method of claim 10, wherein the additional antiviral agent is selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.
 12. A method of treating a warm-blooded animal infected by a respiratory syncytial virus, or being at risk of infection by a respiratory syncytial virus, comprising administering to the warm-blooded animal an anti-virally effective amount of the compound of claim 1 and an additional antiviral agent.
 13. The method of claim 12, wherein the additional antiviral agent is selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.
 14. A compound which is 2-[6-{[2-(3-hydroxy-propyl)-5-methyl-phenylamino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol and pharmaceutically acceptable salts thereof.
 15. A pharmaceutical composition comprising the compound of claim 14 and a pharmaceutically acceptable carrier.
 16. A method for treating a respiratory syncytial viral infection comprising administering to a human subject in need thereof an anti-virally effective amount of the compound of claim
 14. 17. A method for treating a respiratory syncytial viral infection comprising administering to a human subject in need thereof an anti-virally effective amount of the composition of claim
 15. 18. A pharmaceutical composition made by mixing the compound of claim 14 and a pharmaceutically acceptable carrier.
 19. A process for making a pharmaceutical composition comprising mixing the compound of claim 14 and a pharmaceutically acceptable carrier.
 20. The pharmaceutical composition of claim 15, further comprising an additional antiviral agent.
 21. The pharmaceutical composition of claim 15, further comprising an additional antiviral agent selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.
 22. A method of treating a warm-blooded animal infected by a respiratory syncytial virus, or being at risk of infection by a respiratory syncytial virus, comprising administering to the warm-blooded animal an anti-virally effective amount of the compound of claim
 14. 23. A method for treating a respiratory synctial viral infection comprising administering to a human subject in need thereof an anti-virally effective amount of the compound of claim 14, and an additional antiviral agent.
 24. The method of claim 23, wherein the additional antiviral agent is selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.
 25. A method of treating a warm-blooded animal infected by a respiratory syncytial virus, or being at risk of infection by a respiratory syncytial virus, comprising administering to the warm-blooded animal an anti-virally effective amount of the compound of claim 14 and an additional antiviral agent.
 26. The method of claim 25, wherein the additional antiviral agent is selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.
 27. A compound which is 2-[6-{[2-(3-hydroxy-propyl)-5-methyl-phenylamino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol.
 28. A pharmaceutical composition comprising the compound of claim 27 and a pharmaceutically acceptable carrier.
 29. A method for treating a respiratory syncytial viral infection comprising administering to a human subject in need thereof an anti-virally effective amount of the compound of claim
 27. 30. The pharmaceutical composition of claim 28, further comprising an additional antiviral agent.
 31. The pharmaceutical composition of claim 28, further comprising an additional antiviral agent selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.
 32. A method of treating a warm-blooded animal infected by a respiratory syncytial virus, or being at risk of infection by a respiratory syncytial virus, comprising administering to the warm-blooded animal an anti-virally effective amount of the compound of claim
 27. 33. A method for treating a respiratory synctial viral infection comprising administering to a human subject in need thereof an anti-virally effective amount of the compound of claim 27 and an additional antiviral agent.
 34. The method of claim 33, wherein the additional antiviral agent is selected from the group consisting of interferon-beta and tumor necrosis factor-alpha.
 35. A method of treating a warm-blooded animal infected by a respiratory syncytial virus, or being at risk of infection by a respiratory syncytial virus, comprising administering to the warm-blooded animal an anti-virally effective amount of the compound of claim 27 and an additional antiviral agent.
 36. The method of claim 35, wherein the additional antiviral agent is selected from the group consisting of interferon-beta and tumor necrosis factor-alpha. 